Publications - The Institute of Cancer Research, London

Publications Highlights View all by category

Types of Publications

Journals
Conference

Journal Articles

Larkin, J., Brown, M.P., Arance, A.M., Hauschild, A., Queirolo, P., Vecchio, M.D., Ascierto, P.A., Krajsová, I., Schachter, J., Neyns, B., et al. (2019). An open-label, multicentre safety study of vemurafenib in patients with BRAFV600-mutant metastatic melanoma: final analysis and a validated prognostic scoring system. European journal of cancer, Vol.107, pp. 175-185.

Larkin, J., Minor, D., D'Angelo, S., Neyns, B., Smylie, M., Miller, W.H., Gutzmer, R., Linette, G., Chmielowski, B., Lao, C.D., et al. (2018). Overall Survival in Patients With Advanced Melanoma Who Received Nivolumab Versus Investigator’s Choice Chemotherapy in CheckMate 037: A Randomized, Controlled, Open-Label Phase III Trial. Journal of clinical oncology, Vol.36 (4), pp. 383-390.

Lim, K.H., Spain, L., Barker, C., Georgiou, A., Walls, G., Gore, M., Turajlic, S., Board, R., Larkin, J.M. & Lorigan, P., et al. (2018). Contemporary outcomes from the use of regular imaging to detect relapse in high-risk cutaneous melanoma. Esmo open, Vol.3 (2), pp. e000317-e000317.

Smith, H.G., Joshi, K., Strauss, D.C., Hayes, A.J., Larkin, J. & Smith, M.J. (2018). The Impact of Effective Systemic Therapies on Surgery for Stage IV Metastatic Melanoma. Annals of surgical oncology, Vol.25, pp. S41-S41.

Grob, J.J., Schadendorf, D., Lorigan, P., Ascierto, P., Larkin, J., Nathan, P., Robert, C., Hauschild, A., Weber, J., Daud, A., et al. (2018). Eighth American Joint Committee on Cancer (AJCC) melanoma classification: Let us reconsider stage III. European journal of cancer, Vol.91, pp. 168-170.

Valpione, S., Carlino, M.S., Mangana, J., Mooradian, M.J., McArthur, G., Schadendorf, D., Hauschild, A., Menzies, A.M., Arance, A., Ascierto, P.A., et al. (2018). Rechallenge with BRAF-directed treatment in metastatic melanoma: A multi-institutional retrospective study. European journal of cancer, Vol.91, pp. 116-124.

Dréno, B., Ascierto, P.A., Atkinson, V., Liszkay, G., Maio, M., Mandalà, M., Demidov, L., Stroyakovskiy, D., Thomas, L., de la Cruz-Merino, L., et al. (2018). Health-related quality of life impact of cobimetinib in combination with vemurafenib in patients with advanced or metastatic BRAFV600 mutation–positive melanoma. British journal of cancer, Vol.118 (6), pp. 777-784.

Hayes, A.J. & Larkin, J. (2018). BMI and outcomes in melanoma: more evidence for the obesity paradox. The lancet oncology, Vol.19 (3), pp. 269-270.

Yip, K., Melcher, A., Harrington, K., Illidge, T., Nobes, J., Webster, A., Smith, D., Lorigan, P., Nathan, P. & Larkin, J., et al. (2018). Pembrolizumab in Combination with Radiotherapy for Metastatic Melanoma — Introducing the PERM Trial. Clinical oncology, Vol.30 (4), pp. 201-203.

Choueiri, T.K., Larkin, J., Oya, M., Thistlethwaite, F., Martignoni, M., Nathan, P., Powles, T., McDermott, D., Robbins, P.B., Chism, D.D., et al. (2018). Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial. The lancet oncology, Vol.19 (4), pp. 451-460.

Arce Vargas, F., Furness, A.J., Litchfield, K., Joshi, K., Rosenthal, R., Ghorani, E., Solomon, I., Lesko, M.H., Ruef, N., Roddie, C., et al. (2018). Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies. Cancer cell, Vol.33 (4), pp. 649-663.e4.

Turajlic, S., Xu, H., Litchfield, K., Rowan, A., Horswell, S., Chambers, T., O’Brien, T., Lopez, J.I., Watkins, T.B., Nicol, D., et al. (2018). Deterministic Evolutionary Trajectories Influence Primary Tumor Growth: TRACERx Renal. Cell, Vol.173 (3), pp. 595-610.e11.

Turajlic, S., Xu, H., Litchfield, K., Rowan, A., Chambers, T., Lopez, J.I., Nicol, D., O’Brien, T., Larkin, J., Horswell, S., et al. (2018). Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal. Cell, Vol.173 (3), pp. 581-594.e12.

Mitchell, T.J., Turajlic, S., Rowan, A., Nicol, D., Farmery, J.H., O’Brien, T., Martincorena, I., Tarpey, P., Angelopoulos, N., Yates, L.R., et al. (2018). Timing the Landmark Events in the Evolution of Clear Cell Renal Cell Cancer: TRACERx Renal. Cell, Vol.173 (3), pp. 611-623.e17.

Wongchenko, M.J., Ribas, A., Dréno, B., Ascierto, P.A., McArthur, G.A., Gallo, J.D., Rooney, I.A., Hsu, J., Koeppen, H., Yan, Y., et al. (2018). Association of programmed death ligand-1 (PD-L1) expression with treatment outcomes in patients with BRAF mutation-positive melanoma treated with vemurafenib or cobimetinib combined with vemurafenib. Pigment cell & melanoma research, Vol.31 (4), pp. 516-522.

Eggermont, A.M., Blank, C.U., Mandala, M., Long, G.V., Atkinson, V., Dalle, S., Haydon, A., Lichinitser, M., Khattak, A., Carlino, M.S., et al. (2018). Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma. New england journal of medicine, Vol.378 (19), pp. 1789-1801.

Sun, M., Marconi, L., Eisen, T., Escudier, B., Giles, R.H., Haas, N.B., Harshman, L.C., Quinn, D.I., Larkin, J., Pal, S.K., et al. (2018). Adjuvant Vascular Endothelial Growth Factor–targeted Therapy in Renal Cell Carcinoma: A Systematic Review and Pooled Analysis. European urology, Vol.74 (5), pp. 611-620.

Spain, L., Walls, G., Messiou, C., Turajlic, S., Gore, M. & Larkin, J. (2017). Efficacy and toxicity of rechallenge with combination immune checkpoint blockade in metastatic melanoma: a case series. Cancer immunology, immunotherapy, Vol.66 (1), pp. 113-117.

Long, G.V., Flaherty, K.T., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., Garbe, C., Jouary, T., Hauschild, A., et al. (2017). Dabrafenib plus trametinib versus dabrafenib monotherapy in patients with metastatic BRAF V600E/K-mutant melanoma: long-term survival and safety analysis of a phase 3 study. Annals of oncology, Vol.28 (7), pp. 1631-1639.

Wongchenko, M.J., McArthur, G.A., Dréno, B., Larkin, J., Ascierto, P.A., Sosman, J., Andries, L., Kockx, M., Hurst, S.D., Caro, I., et al. (2017). Gene Expression Profiling in BRAF-Mutated Melanoma Reveals Patient Subgroups with Poor Outcomes to Vemurafenib That May Be Overcome by Cobimetinib Plus Vemurafenib. Clinical cancer research, Vol.23 (17), pp. 5238-5245.

Long, G.V., Weber, J.S., Larkin, J., Atkinson, V., Grob, J.-., Schadendorf, D., Dummer, R., Robert, C., Márquez-Rodas, I., McNeil, C., et al. (2017). Nivolumab for Patients With Advanced Melanoma Treated Beyond Progression. Jama oncology, Vol.3 (11), pp. 1511-1511.

Haanen, J.B., Carbonnel, F., Robert, C., Kerr, K.M., Peters, S., Larkin, J. & Jordan, K. (2017). Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†. Annals of oncology, Vol.28 (suppl_4), pp. iv119-iv142.

Chapman, P.B., Robert, C., Larkin, J., Haanen, J.B., Ribas, A., Hogg, D., Hamid, O., Ascierto, P.A., Testori, A., Lorigan, P.C., et al. (2017). Vemurafenib in patients with BRAFV600 mutation-positive metastatic melanoma: final overall survival results of the randomized BRIM-3 study. Ann oncol, Vol.28 (10), pp. 2581-2587. show abstract

Background: The BRIM-3 trial showed improved progression-free survival (PFS) and overall survival (OS) for vemurafenib compared with dacarbazine in treatment-naive patients with BRAFV600 mutation-positive metastatic melanoma. We present final OS data from BRIM-3. Patients and methods: Patients were randomly assigned in a 1 : 1 ratio to receive vemurafenib (960 mg twice daily) or dacarbazine (1000 mg/m2 every 3 weeks). OS and PFS were co-primary end points. OS was assessed in the intention-to-treat population, with and without censoring of data for dacarbazine patients who crossed over to vemurafenib. Results: Between 4 January 2010 and 16 December 2010, a total of 675 patients were randomized to vemurafenib (n = 337) or dacarbazine (n = 338, of whom 84 crossed over to vemurafenib). At the time of database lock (14 August 2015), median OS, censored at crossover, was significantly longer for vemurafenib than for dacarbazine {13.6 months [95% confidence interval (CI) 12.0-15.4] versus 9.7 months [95% CI 7.9-12.8; hazard ratio (HR) 0.81 [95% CI 0.67-0.98]; P = 0.03}, as was median OS without censoring at crossover [13.6 months (95% CI 12.0-15.4) versus 10.3 months (95% CI 9.1-12.8); HR 0.81 (95% CI 0.68-0.96); P = 0.01]. Kaplan-Meier estimates of OS rates for vemurafenib versus dacarbazine were 56% versus 46%, 30% versus 24%, 21% versus 19% and 17% versus 16% at 1, 2, 3 and 4 years, respectively. Overall, 173 of the 338 patients (51%) in the dacarbazine arm and 175 of the 337 (52%) of those in the vemurafenib arm received subsequent anticancer therapies, most commonly ipilimumab. Safety data were consistent with the primary analysis. Conclusions: Vemurafenib continues to be associated with improved median OS in the BRIM-3 trial after extended follow-up. OS curves converged after ≈3 years, likely as a result of crossover from dacarbazine to vemurafenib and receipt of subsequent anticancer therapies. ClinicalTrials.gov: NCT01006980..

Grande, E., Glen, H., Aller, J., Argenziano, G., Lamas, M.J., Ruszniewski, P., Zamorano, J.L., Edmonds, K., Sarker, S., Staehler, M., et al. (2017). Recommendations on managing lenvatinib and everolimus in patients with advanced or metastatic renal cell carcinoma. Expert opinion on drug safety, Vol.16 (12), pp. 1413-1426.

Weber, J.S., Hodi, F.S., Wolchok, J.D., Topalian, S.L., Schadendorf, D., Larkin, J., Sznol, M., Long, G.V., Li, H., Waxman, I.M., et al. (2017). Safety Profile of Nivolumab Monotherapy: A Pooled Analysis of Patients With Advanced Melanoma. Journal of clinical oncology, Vol.35 (7), pp. 785-792.

O’reilly, A. & Larkin, J. (2017). Checkpoint inhibitors in advanced melanoma: effect on the field of immunotherapy. Expert review of anticancer therapy, Vol.17 (7), pp. 647-655.

O’Reilly, A. & Larkin, J. (2017). The safety of nivolumab for the treatment of metastatic melanoma. Expert opinion on drug safety, Vol.16 (8), pp. 955-961.

Rothermundt, C., von Rappard, J., Eisen, T., Escudier, B., Grünwald, V., Larkin, J., McDermott, D., Oldenburg, J., Porta, C., Rini, B., et al. (2017). Second-line treatment for metastatic clear cell renal cell cancer: experts’ consensus algorithms. World journal of urology, Vol.35 (4), pp. 641-648.

Morganstein, D.L., Lai, Z., Spain, L., Diem, S., Levine, D., Mace, C., Gore, M. & Larkin, J. (2017). Thyroid abnormalities following the use of cytotoxic T-lymphocyte antigen-4 and programmed death receptor protein-1 inhibitors in the treatment of melanoma. Clinical endocrinology, Vol.86 (4), pp. 614-620.

Bracarda, S., Negrier, S., Casper, J., Porta, C., Schmidinger, M., Larkin, J., Gross Goupil, M. & Escudier, B. (2017). How clinical practice is changing the rules: the sunitinib 2/1 schedule in metastatic renal cell carcinoma. Expert review of anticancer therapy, Vol.17 (3), pp. 227-233.

Spain, L., Schmid, T., Gore, M. & Larkin, J. (2017). Efficacy of the combination of ipilimumab and nivolumab following progression on pembrolizumab in advanced melanoma with poor risk features. European journal of cancer, Vol.75, pp. 243-244.

Bowyer, S., Prithviraj, P., Lorigan, P., Larkin, J., McArthur, G., Atkinson, V., Millward, M., Khou, M., Diem, S., Ramanujam, S., et al. (2017). Reply to ‘Comment on ‘Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy’’. British journal of cancer, Vol.116 (8), pp. e15-e15.

Arce Vargas, F., Furness, A.J., Solomon, I., Joshi, K., Mekkaoui, L., Lesko, M.H., Miranda Rota, E., Dahan, R., Georgiou, A., Sledzinska, A., et al. (2017). Fc-Optimized Anti-CD25 Depletes Tumor-Infiltrating Regulatory T Cells and Synergizes with PD-1 Blockade to Eradicate Established Tumors. Immunity, Vol.46 (4), pp. 577-586.

Dreno, B., Ribas, A., Larkin, J., Ascierto, P.A., Hauschild, A., Thomas, L., Grob, J.-., Koralek, D.O., Rooney, I., Hsu, J.J., et al. (2017). Incidence, course, and management of toxicities associated with cobimetinib in combination with vemurafenib in the coBRIM study. Annals of oncology, Vol.28 (5), pp. 1137-1144.

Wolchok, J.D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-., Cowey, C.L., Lao, C.D., Wagstaff, J., Schadendorf, D., Ferrucci, P.F., et al. (2017). Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. New england journal of medicine, Vol.377 (14), pp. 1345-1356.

Stewart, G.D., Aitchison, M., Bex, A., Larkin, J., Lawless, C., Méjean, A., Nathan, P., Oades, G., Patard, J.-., Paul, J., et al. (2017). Cytoreductive Nephrectomy in the Tyrosine Kinase Inhibitor Era: A Question That May Never Be Answered. European urology, Vol.71 (6), pp. 845-847.

Larkin, J., Chmielowski, B., Lao, C.D., Hodi, F.S., Sharfman, W., Weber, J., Suijkerbuijk, K.P., Azevedo, S., Li, H., Reshef, D., et al. (2017). Neurologic Serious Adverse Events Associated with Nivolumab Plus Ipilimumab or Nivolumab Alone in Advanced Melanoma, Including a Case Series of Encephalitis. The oncologist, Vol.22 (6), pp. 709-718.

Helgadottir, H., Kis, L., Ljungman, P., Larkin, J., Kefford, R., Ascierto, P.A., Hansson, J. & Masucci, G. (2017). Lethal aplastic anemia caused by dual immune checkpoint blockade in metastatic melanoma. Annals of oncology, Vol.28 (7), pp. 1672-1673.

Blank, C.U., Larkin, J., Arance, A.M., Hauschild, A., Queirolo, P., Del Vecchio, M., Ascierto, P.A., Krajsova, I., Schachter, J., Neyns, B., et al. (2017). Open-label, multicentre safety study of vemurafenib in 3219 patients with BRAF V600 mutation-positive metastatic melanoma: 2-year follow-up data and long-term responders' analysis. European journal of cancer, Vol.79, pp. 176-184.

Colomba, E., Le Teuff, G., Eisen, T., Stewart, G.D., Fife, K., Larkin, J., Biondo, A., Pickering, L., Srinivasan, A., Boyle, H., et al. (2017). Metastatic chromophobe renal cell carcinoma treated with targeted therapies: A Renal Cross Channel Group study. European journal of cancer, Vol.80, pp. 55-62.

Scelo, G., Purdue, M.P., Brown, K.M., Johansson, M., Wang, Z., Eckel-Passow, J.E., Ye, Y., Hofmann, J.N., Choi, J., Foll, M., et al. (2017). Genome-wide association study identifies multiple risk loci for renal cell carcinoma. Nature communications, Vol.8 (1).

Turajlic, S., Litchfield, K., Xu, H., Rosenthal, R., McGranahan, N., Reading, J.L., Wong, Y.N., Rowan, A., Kanu, N., Al Bakir, M., et al. (2017). Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. The lancet oncology, Vol.18 (8), pp. 1009-1021.

Matoori, S., Thian, Y., Koh, D.-., Sohaib, A., Larkin, J., Pickering, L. & Gutzeit, A. (2017). Contrast-Enhanced CT Density Predicts Response to Sunitinib Therapy in Metastatic Renal Cell Carcinoma Patients. Translational oncology, Vol.10 (4), pp. 679-685.

Schadendorf, D., Larkin, J., Wolchok, J., Hodi, F.S., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-., Cowey, C.L., Lao, C., et al. (2017). Health-related quality of life results from the phase III CheckMate 067 study. European journal of cancer, Vol.82, pp. 80-91.

Ugurel, S., Röhmel, J., Ascierto, P.A., Flaherty, K.T., Grob, J.J., Hauschild, A., Larkin, J., Long, G.V., Lorigan, P., McArthur, G.A., et al. (2017). Survival of patients with advanced metastatic melanoma: the impact of novel therapies–update 2017. European journal of cancer, Vol.83, pp. 247-257.

Long, G.V., Hauschild, A., Santinami, M., Atkinson, V., Mandalà, M., Chiarion-Sileni, V., Larkin, J., Nyakas, M., Dutriaux, C., Haydon, A., et al. (2017). Adjuvant Dabrafenib plus Trametinib in Stage IIIBRAF-Mutated Melanoma. New england journal of medicine, Vol.377 (19), pp. 1813-1823.

Weber, J., Mandala, M., Del Vecchio, M., Gogas, H.J., Arance, A.M., Cowey, C.L., Dalle, S., Schenker, M., Chiarion-Sileni, V., Marquez-Rodas, I., et al. (2017). Adjuvant Nivolumab versus Ipilimumab in Resected Stage III or IV Melanoma. New england journal of medicine, Vol.377 (19), pp. 1824-1835.

D’Angelo, S.P., Larkin, J., Sosman, J.A., Lebbé, C., Brady, B., Neyns, B., Schmidt, H., Hassel, J.C., Hodi, F.S., Lorigan, P., et al. (2017). Efficacy and Safety of Nivolumab Alone or in Combination With Ipilimumab in Patients With Mucosal Melanoma: A Pooled Analysis. Journal of clinical oncology, Vol.35 (2), pp. 226-235.

Schachter, J., Ribas, A., Long, G.V., Arance, A., Grob, J.-., Mortier, L., Daud, A., Carlino, M.S., McNeil, C., Lotem, M., et al. (2017). Pembrolizumab versus ipilimumab for advanced melanoma: final overall survival results of a multicentre, randomised, open-label phase 3 study (KEYNOTE-006). The lancet, Vol.390 (10105), pp. 1853-1862.

Machiela, M.J., Hofmann, J.N., Carreras-Torres, R., Brown, K.M., Johansson, M., Wang, Z., Foll, M., Li, P., Rothman, N., Savage, S.A., et al. (2017). Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma. European urology, Vol.72 (5), pp. 747-754.

Hsieh, J.J., Purdue, M.P., Signoretti, S., Swanton, C., Albiges, L., Schmidinger, M., Heng, D.Y., Larkin, J. & Ficarra, V. (2017). Renal cell carcinoma. Nature reviews disease primers, Vol.3 (1).

de la Cruz-Merino, L., Di Guardo, L., Grob, J.-., Venosa, A., Larkin, J., McArthur, G.A., Ribas, A., Ascierto, P.A., Evans, J.T., Gomez-Escobar, A., et al. (2017). Clinical features of serous retinopathy observed with cobimetinib in patients with BRAF-mutated melanoma treated in the randomized coBRIM study. Journal of translational medicine, Vol.15 (1).

Schadendorf, D., Wolchok, J.D., Hodi, F.S., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.-., Cowey, C.L., Lao, C.D., Chesney, J., et al. (2017). Efficacy and Safety Outcomes in Patients With Advanced Melanoma Who Discontinued Treatment With Nivolumab and Ipilimumab Because of Adverse Events: A Pooled Analysis of Randomized Phase II and III Trials. Journal of clinical oncology, Vol.35 (34), pp. 3807-3814.

(2017). Nivolumab and Ipilimumab in Advanced Melanoma. New england journal of medicine, Vol.377 (25), pp. 2503-2504.

Flynn, M.J. & Larkin, J.M. (2017). Novel combination strategies for enhancing efficacy of immune checkpoint inhibitors in the treatment of metastatic solid malignancies. Expert opinion on pharmacotherapy, Vol.18 (14), pp. 1477-1490.

Seifert, H., Hirata, E., Gore, M., Khabra, K., Messiou, C., Larkin, J. & Sahai, E. (2016). Extrinsic factors can mediate resistance to BRAF inhibition in central nervous system melanoma metastases. Pigment cell & melanoma research, Vol.29 (1), pp. 92-100.

Bridgeman, V., Wan, E., Foo, S., Nathan, M., Welti, J., Frentzas, S., Vermeulen, P., Preece, N., Springer, C., Powles, T., et al. (2016). Preclinical evidence that trametinib enhances the response to anti-angiogenic tyrosine kinase inhibitors in renal cell carcinoma. Molecular cancer therapeutics, Vol.1 (15), pp. 172-183.

Ugurel, S., Röhmel, J., Ascierto, P.A., Flaherty, K.T., Grob, J.J., Hauschild, A., Larkin, J., Long, G.V., Lorigan, P., McArthur, G.A., et al. (2016). Survival of patients with advanced metastatic melanoma: The impact of novel therapies. European journal of cancer, Vol.53, pp. 125-134.

Motzer, R.J., Hutson, T.E., Ren, M., Dutcus, C. & Larkin, J. (2016). Independent assessment of lenvatinib plus everolimus in patients with metastatic renal cell carcinoma. The lancet oncology, Vol.17 (1), pp. e4-e5.

Atkins, M.B. & Larkin, J. (2016). Immunotherapy Combined or Sequenced With Targeted Therapy in the Treatment of Solid Tumors: Current Perspectives. Jnci: journal of the national cancer institute, Vol.108 (6).

Porta, C., Tortora, G., Larkin, J.M. & Hutson, T.E. (2016). Management of poor-risk metastatic renal cell carcinoma: current approaches, the role of temsirolimus and future directions. Future oncology, Vol.12 (4), pp. 533-549.

Diem, S., Kasenda, B., Spain, L., Martin-Liberal, J., Marconcini, R., Gore, M. & Larkin, J. (2016). Serum lactate dehydrogenase as an early marker for outcome in patients treated with anti-PD-1 therapy in metastatic melanoma. British journal of cancer, Vol.114 (3), pp. 256-261.

Spain, L., Julve, M. & Larkin, J. (2016). Combination dabrafenib and trametinib in the management of advanced melanoma with BRAFV600 mutations. Expert opinion on pharmacotherapy, Vol.17 (7), pp. 1031-1038.

Spain, L. & Larkin, J. (2016). Combination immune checkpoint blockade with ipilimumab and nivolumab in the management of advanced melanoma. Expert opinion on biological therapy, Vol.16 (3), pp. 389-396.

Spain, L., Diem, S. & Larkin, J. (2016). Management of toxicities of immune checkpoint inhibitors. Cancer treatment reviews, Vol.44, pp. 51-60.

Thomas, C.L., Mortimer, P.S., Larkin, J.M., Basu, T.N., Gore, M.E. & Fearfield, L. (2016). A mitogen-activated protein kinase kinase inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma. Clinical and experimental dermatology, Vol.41 (3), pp. 267-271.

Seifert, H., Fisher, R., Martin-Liberal, J., Edmonds, K., Hughes, P., Khabra, K., Gore, M. & Larkin, J. (2016). Prognostic markers and tumour growth kinetics in melanoma patients progressing on vemurafenib. Melanoma research, Vol.26 (2), pp. 138-144.

Gravis, G., Chanez, B., Derosa, L., Beuselinck, B., Barthelemy, P., Laguerre, B., Brachet, P.-., Joly, F., Escudier, B., Harrison, D.J., et al. (2016). Effect of glandular metastases on overall survival of patients with metastatic clear cell renal cell carcinoma in the antiangiogenic therapy era. Urologic oncology: seminars and original investigations, Vol.34 (4), pp. 167.e17-167.e23.

Powles, T., Brown, J., Larkin, J., Jones, R., Ralph, C., Hawkins, R., Chowdhury, S., Boleti, E., Bhal, A., Fife, K., et al. (2016). A randomized, double-blind phase II study evaluating cediranib versus cediranib and saracatinib in patients with relapsed metastatic clear-cell renal cancer (COSAK). Annals of oncology, Vol.27 (5), pp. 880-886.

Bowyer, S., Prithviraj, P., Lorigan, P., Larkin, J., McArthur, G., Atkinson, V., Millward, M., Khou, M., Diem, S., Ramanujam, S., et al. (2016). Efficacy and toxicity of treatment with the anti-CTLA-4 antibody ipilimumab in patients with metastatic melanoma after prior anti-PD-1 therapy. British journal of cancer, Vol.114 (10), pp. 1084-1089.

Spain, L., Higgins, R., Gopalakrishnan, K., Turajlic, S., Gore, M. & Larkin, J. (2016). Acute renal allograft rejection after immune checkpoint inhibitor therapy for metastatic melanoma. Annals of oncology, Vol.27 (6), pp. 1135-1137.

Spain, L., Larkin, J. & Martin-Liberal, J. (2016). Determining predictive factors for immune checkpoint inhibitor toxicity: Response to Letter to the Editors “A case report of insulin-dependent diabetes as immune-related toxicity of pembrolizumab: presentation, management and outcome”. Cancer immunology, immunotherapy, Vol.65 (6), pp. 769-770.

Spain, L. & Larkin, J. (2016). Weighing up the pros and cons of immune checkpoint inhibitors in the treatment of melanoma. Immunotherapy, Vol.8 (6), pp. 677-679.

Rini, B.I., Dorff, T.B., Elson, P., Rodriguez, C.S., Shepard, D., Wood, L., Humbert, J., Pyle, L., Wong, Y.-., Finke, J.H., et al. (2016). Active surveillance in metastatic renal-cell carcinoma: a prospective, phase 2 trial. The lancet oncology, Vol.17 (9), pp. 1317-1324.

Ascierto, P.A., McArthur, G.A., Dréno, B., Atkinson, V., Liszkay, G., Di Giacomo, A.M., Mandalà, M., Demidov, L., Stroyakovskiy, D., Thomas, L., et al. (2016). Cobimetinib combined with vemurafenib in advanced BRAFV600-mutant melanoma (coBRIM): updated efficacy results from a randomised, double-blind, phase 3 trial. The lancet oncology, Vol.17 (9), pp. 1248-1260.

Spain, L., Goode, E., McGovern, Y., Joshi, K. & Larkin, J. (2016). The combination of vemurafenib and cobimetinib in advanced melanoma. Expert opinion on orphan drugs, Vol.4 (11), pp. 1105-1111.

Turajlic, S. & Larkin, J. (2016). Systemic treatment of advanced papillary renal cell carcinoma: Where next?. European journal of cancer, Vol.69, pp. 223-225.

Joshi, K., Furness, A.J., Oakes, T., Heather, J., Spain, L.A., Wong, Y.N., Ben Aissa, A., Stares, M., Smith, M.J., Strauss, D.C., et al. (2016). Defining the mechanisms of response and resistance to anti-PD-1 therapy: An exploratory phase II study of pembrolizumab in advanced melanoma (ADAPTeM). Journal of clinical oncology, Vol.34 (15_suppl), pp. TPS9599-TPS9599.

Spain, L., Walls, G., Julve, M., O'Meara, K., Schmid, T., Kalaitzaki, E., Turajlic, S., Gore, M., Rees, J. & Larkin, J., et al. (2016). Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Ann oncol, .

Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-., Cowey, C.L., Lao, C.D., Wagstaff, J., Hogg, D., Hill, A., Carlino, M.S., et al. (2016). Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients with advanced melanoma (MEL) (CheckMate 067). Oncology research and treatment, Vol.39, pp. 40-40.

Lorigan, P., Ascierto, P.A., Dummer, R., Eggermont, A.M., Flaherty, K.T., Garbe, C., Gogas, H., Hauschild, A., Kefford, R.F., Kirkwood, J.M., et al. (2015). Expanded access programmes: patient interests versus clinical trial integrity. Lancet oncology, Vol.16 (1), pp. 15-17.

Larkin, J., Lao, C.D., Urba, W.J., McDermott, D.F., Horak, C., Jiang, J. & Wolchok, J.D. (2015). Efficacy and Safety of Nivolumab in Patients With BRAF V600 Mutant and BRAF Wild-Type Advanced Melanoma. Jama oncology, Vol.1 (4), pp. 433-433.

Rothermundt, C., Bailey, A., Cerbone, L., Eisen, T., Escudier, B., Gillessen, S., Grunwald, V., Larkin, J., McDermott, D., Oldenburg, J., et al. (2015). Algorithms in the First-Line Treatment of Metastatic Clear Cell Renal Cell Carcinoma--Analysis Using Diagnostic Nodes. The oncologist, Vol.20 (9), pp. 1028-1035.

Coupe, N., Corrie, P., Hategan, M., Larkin, J., Gore, M., Gupta, A., Wise, A., Suter, S., Ciria, C., Love, S., et al. (2015). PACMEL: a phase 1 dose escalation trial of trametinib (GSK1120212) in combination with paclitaxel. Eur j cancer, Vol.51 (3), pp. 359-366. show abstract

Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, D., Dummer, R., Smylie, M., Rutkowski, P., et al. (2015). Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New england journal of medicine, Vol.373 (1), pp. 23-34.

Larkin, J., Paine, A., Foley, G., Mitchell, S. & Chen, C. (2015). First-line treatment in the management of advanced renal cell carcinoma: systematic review and network meta-analysis. Expert opinion on pharmacotherapy, Vol.16 (13), pp. 1915-1927.

Martin-Liberal, J., Kordbacheh, T. & Larkin, J. (2015). Safety of pembrolizumab for the treatment of melanoma. Expert opinion on drug safety, Vol.14 (6), pp. 957-964.

Weber, J.S., D'Angelo, S.P., Minor, D., Hodi, F.S., Gutzmer, R., Neyns, B., Hoeller, C., Khushalani, N.I., Miller, W.H., Lao, C.D., et al. (2015). Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The lancet oncology, Vol.16 (4), pp. 375-384.

Sinha, R., Larkin, J. & Fearfield, L. (2015). Clinical resolution of vemurafenib-induced squamous cell carcinoma with topical 5-fluorouracil. British journal of dermatology, Vol.172 (4), pp. 1135-1136.

Hirata, E., Girotti, M.R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., Larkin, J., Marais, R. & Sahai, E. (2015). Intravital Imaging Reveals How BRAF Inhibition Generates Drug-Tolerant Microenvironments with High Integrin β1/FAK Signaling. Cancer cell, Vol.27 (4), pp. 574-588.

Kovac, M., Navas, C., Horswell, S., Salm, M., Bardella, C., Rowan, A., Stares, M., Castro-Giner, F., Fisher, R., de Bruin, E.C., et al. (2015). Recurrent chromosomal gains and heterogeneous driver mutations characterise papillary renal cancer evolution. Nature communications, Vol.6 (1).

Schadendorf, D., Amonkar, M.M., Stroyakovskiy, D., Levchenko, E., Gogas, H., de Braud, F., Grob, J.-., Bondarenko, I., Garbe, C., Lebbe, C., et al. (2015). Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. European journal of cancer, Vol.51 (7), pp. 833-840.

Thomas, C.L., Mortimer, P.S., Larkin, J.M., Basu, T.N., Gore, M.E. & Fearfield, L. (2015). MEK-inhibitor induced compound skin toxicity with oedema in metastatic malignant melanoma: a case series. Australasian journal of dermatology, Vol.56, pp. 78-78.

Bex, A., Larkin, J. & Voss, M. (2015). Challenging the Treatment Paradigm for Advanced Renal Cell Carcinoma: A Review of Systemic and Localized Therapies. American society of clinical oncology educational book, (35), pp. e239-e247.

Motzer, R.J., Escudier, B., McDermott, D.F., George, S., Hammers, H.J., Srinivas, S., Tykodi, S.S., Sosman, J.A., Procopio, G., Plimack, E.R., et al. (2015). Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. New england journal of medicine, Vol.373 (19), pp. 1803-1813.

Martin-Liberal, J., Furness, A.J., Joshi, K., Peggs, K.S., Quezada, S.A. & Larkin, J. (2015). Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer immunology, immunotherapy, Vol.64 (6), pp. 765-767.

Yousaf, N., Davidson, M., Goode, E., Thomas, C., Hung, R., Gore, M. & Larkin, J. (2015). The cost of ipilimumab toxicity. Melanoma research, Vol.25 (3), pp. 259-264.

Pickering, L.M. & Larkin, J. (2015). Carbonic anhydrase IX in resected clear cell RCC. Nature reviews urology, Vol.12 (6), pp. 309-310.

Long, G.V., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., Garbe, C., Jouary, T., Hauschild, A., Grob, J.-., et al. (2015). Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. The lancet, Vol.386 (9992), pp. 444-451.

Wolchok, J.D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, D., Ferrucci, P.F., Smylie, M., et al. (2015). CHECKMATE 067: A PHASE III RANDOMIZED DOUBLE-BLIND STUDY OF NIVOLUMAB (NIVO) MONOTHERAPY OR NIVO COMBINED WITH IPILIMUMAB (IPI) VERSUS IPI MONOTHERAPY IN PREVIOUSLY UNTREATED PATIENTS (PTS) WITH ADVANCED MELANOMA (MEL). Asia-pacific journal of clinical oncology, Vol.11, pp. 68-68.

Gulati, S., Turajlic, S., Larkin, J., Bates, P.A. & Swanton, C. (2015). Relapse models for clear cell renal carcinoma. The lancet oncology, Vol.16 (8), pp. e376-e378.

(2015). Corrigendum. The journal of pathology, Vol.236 (4), pp. 531-531.

Moriceau, G., Hugo, W., Hong, A., Shi, H., Kong, X., Yu, C.C., Koya, R.C., Samatar, A.A., Khanlou, N., Braun, J., et al. (2015). Tunable-combinatorial mechanisms of acquired resistance limit the efficacy of BRAF/MEK cotargeting but result in melanoma drug addiction. Cancer cell, Vol.27 (2), pp. 240-256. show abstract

Soultati, A., Stares, M., Swanton, C., Larkin, J. & Turajlic, S. (2015). How should clinicians address intratumour heterogeneity in clear cell renal cell carcinoma?. Current opinion in urology, Vol.25 (5), pp. 358-366.

Sinha, R., Larkin, J., Gore, M. & Fearfield, L. (2015). Cutaneous toxicities associated with vemurafenib therapy in 107 patients withBRAFV600E mutation-positive metastatic melanoma, including recognition and management of rare presentations. British journal of dermatology, Vol.173 (4), pp. 1024-1031.

Turajlic, S., Larkin, J. & Swanton, C. (2015). Academically led clinical trials: challenges and opportunities: Figure 1. Annals of oncology, Vol.26 (10), pp. 2010-2011.

Ahmad, S.S., Qian, W., Ellis, S., Mason, E., Khattak, M.A., Gupta, A., Shaw, H., Quinton, A., Kovarikova, J., Thillai, K., et al. (2015). Ipilimumab in the real world. Melanoma research, Vol.25 (5), pp. 432-442.

Motzer, R., Hutson, T., Glen, H., Michaelson, M.D., Molina, A., Eisen, T., Jassem, J., Zolnierek, J., Maroto, P., Mellado, B., et al. (2015). Randomized phase 2 three-arm trial of lenvatinib (LEN), everolimus (EVE), and LEN plus EVE in patients (pts) with metastatic renal cell carcinoma (mRCC). Oncology research and treatment, Vol.38, pp. 203-204.

Kanu, N., Grönroos, E., Martinez, P., Burrell, R.A., Yi Goh, X., Bartkova, J., Maya-Mendoza, A., Mistrík, M., Rowan, A.J., Patel, H., et al. (2015). SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Oncogene, Vol.34 (46), pp. 5699-5708.

Motzer, R.J., Hutson, T.E., Glen, H., Michaelson, M.D., Molina, A., Eisen, T., Jassem, J., Zolnierek, J., Maroto, J.P., Mellado, B., et al. (2015). Lenvatinib, everolimus, and the combination in patients with metastatic renal cell carcinoma: a randomised, phase 2, open-label, multicentre trial. The lancet oncology, Vol.16 (15), pp. 1473-1482.

Wilkins, A., Furness, A., W Corbett, R., Bloomfield, A., Porta, N., Morris, S., Ali, Z., Larkin, J. & Harrington, K. (2015). The melanoma-specific graded prognostic assessment does not adequately discriminate prognosis in a modern population with brain metastases from malignant melanoma. British journal of cancer, Vol.113 (9), pp. 1275-1281.

Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.-., Cowey, C.L., Lao, C.D., Wagstaff, J., Hogg, D., Hill, A., Carlino, M.S., et al. (2015). EFFICACY AND SAFETY IN KEY PATIENT SUBGROUPS OF NIVOLUMAB (NIVO) ALONE OR COMBINED WITH IPILIMUMAB (IPI) VERSUS IPI ALONE IN TREATMENT-NAIVE PATIENTS WITH ADVANCED MELANOMA (MEL) (CHECKMATE 067). Asia-pacific journal of clinical oncology, Vol.11, pp. 126-126.

Dummer, R., Schadendorf, D., Ascierto, P.A., Larkin, J., Lebbé, C. & Hauschild, A. (2015). Integrating first-line treatment options into clinical practice. Melanoma research, Vol.25 (6), pp. 461-469.

Diem, S., Kasenda, B., Martin-Liberal, J., Lee, A., Chauhan, D., Gore, M. & Larkin, J. (2015). Prognostic score for patients with advanced melanoma treated with ipilimumab. European journal of cancer, Vol.51 (18), pp. 2785-2791.

Turajlic, S., Larkin, J. & Swanton, C. (2015). SnapShot: Renal Cell Carcinoma. Cell, Vol.163 (6), pp. 1556-1556.e1.

Gore, M. & Larkin, J. (2015). Precision oncology: where next?. The lancet oncology, Vol.16 (16), pp. 1593-1595.

Richman, J., Martin-Liberal, J., Diem, S. & Larkin, J. (2015). BRAF and MEK inhibition for the treatment of advanced BRAF mutant melanoma. Expert opinion on pharmacotherapy, Vol.16 (9), pp. 1285-1297.

Jamal-Hanjani, M., Quezada, S.A., Larkin, J. & Swanton, C. (2015). Translational Implications of Tumor Heterogeneity. Clinical cancer research, Vol.21 (6), pp. 1258-1266.

(2015). Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New england journal of medicine, Vol.373 (13), pp. 1270-1271.

Robert, C., Schachter, J., Long, G.V., Arance, A., Grob, J.J., Mortier, L., Daud, A., Carlino, M.S., McNeil, C., Lotem, M., et al. (2015). Pembrolizumab versus Ipilimumab in Advanced Melanoma. New england journal of medicine, Vol.372 (26), pp. 2521-2532.

Martin-Liberal, J. & Larkin, J. (2015). Vemurafenib for the treatment of BRAF mutant metastatic melanoma. Future oncol, Vol.11 (4), pp. 579-589. show abstract

Kasenda, B., Larkin, J. & Gore, M. (2015). Immunotherapies in Early and Advanced Renal Cell Cancer. , , pp. 1-10.

Molina, A.M., Hutson, T.E., Larkin, J., Gold, A.M., Wood, K., Carter, D., Motzer, R. & Michaelson, M.D. (2014). A phase 1b clinical trial of the multi-targeted tyrosine kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC). Cancer chemotherapy and pharmacology, Vol.73 (1), pp. 181-189.

Khattak, M. & Larkin, J. (2014). Sequential therapy with targeted agents in metastatic renal cell carcinoma: beyond second-line and overcoming drug resistance. World j urol, Vol.32 (1), pp. 19-29. show abstract

Gerlinger, M., Horswell, S., Larkin, J., Rowan, A.J., Salm, M.P., Varela, I., Fisher, R., McGranahan, N., Matthews, N., Santos, C., et al. (2014). Genomic architecture and evolution of clear cell renal carcinomas defined by multiregion sequencing. Nature genetics, . show abstract

McArthur, G.A., Chapman, P.B., Robert, C., Larkin, J., Haanen, J.B., Dummer, R., Ribas, A., Hogg, D., Hamid, O., Ascierto, P.A., et al. (2014). Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet oncol, Vol.15 (3), pp. 323-332. show abstract

BACKGROUND: In the BRIM-3 trial, vemurafenib was associated with risk reduction versus dacarbazine of both death and progression in patients with advanced BRAF(V600) mutation-positive melanoma. We present an extended follow-up analysis of the total population and in the BRAF(V600E) and BRAF(V600K) mutation subgroups. METHODS: Patients older than 18 years, with treatment-naive metastatic melanoma and whose tumour tissue was positive for BRAF(V600) mutations were eligible. Patients also had to have a life expectancy of at least 3 months, an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and adequate haematological, hepatic, and renal function. Patients were randomly assigned by interactive voice recognition system to receive either vemurafenib (960 mg orally twice daily) or dacarbazine (1000 mg/m(2) of body surface area intravenously every 3 weeks). Coprimary endpoints were overall survival and progression-free survival, analysed in the intention-to-treat population (n=675), with data censored at crossover. A sensitivity analysis was done. This trial is registered with ClinicalTrials.gov, NCT01006980. FINDINGS: 675 eligible patients were enrolled from 104 centres in 12 countries between Jan 4, 2010, and Dec 16, 2010. 337 patients were randomly assigned to receive vemurafenib and 338 to receive dacarbazine. Median follow-up was 12·5 months (IQR 7·7-16·0) on vemurafenib and 9·5 months (3·1-14·7) on dacarbazine. 83 (25%) of the 338 patients initially randomly assigned to dacarbazine crossed over from dacarbazine to vemurafenib. Median overall survival was significantly longer in the vemurafenib group than in the dacarbazine group (13·6 months [95% CI 12·0-15·2] vs 9·7 months [7·9-12·8]; hazard ratio [HR] 0·70 [95% CI 0·57-0·87]; p=0·0008), as was median progression-free survival (6·9 months [95% CI 6·1-7·0] vs 1·6 months [1·6-2·1]; HR 0·38 [95% CI 0·32-0·46]; p<0·0001). For the 598 (91%) patients with BRAF(V600E) disease, median overall survival in the vemurafenib group was 13·3 months (95% CI 11·9-14·9) compared with 10·0 months (8·0-14·0) in the dacarbazine group (HR 0·75 [95% CI 0·60-0·93]; p=0·0085); median progression-free survival was 6·9 months (95% CI 6·2-7·0) and 1·6 months (1·6-2·1), respectively (HR 0·39 [95% CI 0·33-0·47]; p<0·0001). For the 57 (9%) patients with BRAF(V600K) disease, median overall survival in the vemurafenib group was 14·5 months (95% CI 11·2-not estimable) compared with 7·6 months (6·1-16·6) in the dacarbazine group (HR 0·43 [95% CI 0·21-0·90]; p=0·024); median progression-free survival was 5·9 months (95% CI 4·4-9·0) and 1·7 months (1·4-2·9), respectively (HR 0·30 [95% CI 0·16-0·56]; p<0·0001). The most frequent grade 3-4 events were cutaneous squamous-cell carcinoma (65 [19%] of 337 patients) and keratoacanthomas (34 [10%]), rash (30 [9%]), and abnormal liver function tests (38 [11%]) in the vemurafenib group and neutropenia (26 [9%] of 287 patients) in the dacarbazine group. Eight (2%) patients in the vemurafenib group and seven (2%) in the dacarbazine group had grade 5 events. INTERPRETATION: Inhibition of BRAF with vemurafenib improves survival in patients with the most common BRAF(V600E) mutation and in patients with the less common BRAF(V600K) mutation. FUNDING: F Hoffmann-La Roche-Genentech..

Hutson, T.E., Bukowski, R.M., Rini, B.I., Gore, M.E., Larkin, J.M., Figlin, R.A., Barrios, C.H., Escudier, B., Lin, X., Fly, K., et al. (2014). Efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma. Br j cancer, Vol.110 (5), pp. 1125-1132. show abstract

Larkin, J., Del Vecchio, M., Ascierto, P.A., Krajsova, I., Schachter, J., Neyns, B., Espinosa, E., Garbe, C., Sileni, V.C., Gogas, H., et al. (2014). Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet oncol, Vol.15 (4), pp. 436-444. show abstract

BACKGROUND: The orally available BRAF kinase inhibitor vemurafenib, compared with dacarbazine, shows improved response rates, progression-free survival (PFS), and overall survival in patients with metastatic melanoma that has a BRAF(V600) mutation. We assessed vemurafenib in patients with advanced metastatic melanoma with BRAF(V600) mutations who had few treatment options. METHODS: In an open-label, multicentre study, patients with untreated or previously treated melanoma and a BRAF(V600) mutation received oral vemurafenib 960 mg twice a day. The primary endpoint was safety. All analyses were done on the safety population, which included all patients who received at least one dose of vemurafenib. This report is the third interim analysis of this study. This study is registered with ClinicalTrials.gov, number NCT01307397. FINDINGS: Between March 1, 2011, and Jan 31, 2013, 3226 patients were enrolled in 44 countries. 3222 patients received at least one dose of vemurafenib (safety population). At data cutoff, 868 (27%) patients were on study treatment and 2354 (73%) had withdrawn, mainly because of disease progression. Common adverse events of all grades included rash (1592 [49%]), arthralgia (1259 [39%]), fatigue (1093 [34%]), photosensitivity reaction (994 [31%]), alopecia (826 [26%]), and nausea (628 [19%]). 1480 (46%) patients reported grade 3 or 4 adverse events, including cutaneous squamous cell carcinoma (389 [12%]), rash (155 [5%]), liver function abnormalities (165 [5%]), arthralgia (106 [3%]), and fatigue (93 [3%]). Grade 3 and 4 adverse events were reported more frequently in patients aged 75 years and older (n=257; 152 [59%, 95% CI 53-65] and ten [4%, 2-7], respectively) than in those younger than 75 years (n=2965; 1286 [43%, 42-45] and 82 [3%, 2-3], respectively). INTERPRETATION: Vemurafenib safety in this diverse population of patients with BRAF(V600) mutated metastatic melanoma, who are more representative of routine clinical practice, was consistent with the safety profile shown in the pivotal trials of this drug. FUNDING: F Hoffmann-La Roche..

Martin-Liberal, J., Lagares-Tena, L. & Larkin, J. (2014). Prospects for MEK inhibitors for treating cancer. Expert opin drug saf, Vol.13 (4), pp. 483-495. show abstract

Turajlic, S., Furney, S.J., Stamp, G., Rana, S., Ricken, G., Oduko, Y., Saturno, G., Springer, C., Hayes, A., Gore, M., et al. (2014). Whole-genome sequencing reveals complex mechanisms of intrinsic resistance to BRAF inhibition. Ann oncol, Vol.25 (5), pp. 959-967. show abstract

Kelderman, S., Heemskerk, B., van Tinteren, H., van den Brom, R.R., Hospers, G.A., van den Eertwegh, A.J., Kapiteijn, E.W., de Groot, J.W., Soetekouw, P., Jansen, R.L., et al. (2014). Lactate dehydrogenase as a selection criterion for ipilimumab treatment in metastatic melanoma. Cancer immunology immunotherapy, Vol.63 (5), pp. 449-458.

Gupta, A., Love, S., Schuh, A., Shanyinde, M., Larkin, J.M., Plummer, R., Nathan, P.D., Danson, S., Ottensmeier, C.H., Lorigan, P., et al. (2014). DOC-MEK: a double-blind randomized phase II trial of docetaxel with or without selumetinib in wild-type BRAF advanced melanoma. Annals of oncology, Vol.25 (5), pp. 968-974.

Martin-Liberal, J. & Larkin, J. (2014). New RAF kinase inhibitors in cancer therapy. Expert opin pharmacother, Vol.15 (9), pp. 1235-1245. show abstract

Benson, C., Vitfell-Rasmussen, J., Maruzzo, M., Fisher, C., Tunariu, N., Mitchell, S., Al-Muderis, O., Thway, K., Larkin, J. & Judson, I., et al. (2014). A retrospective study of patients with malignant PEComa receiving treatment with sirolimus or temsirolimus: the Royal Marsden Hospital experience. Anticancer res, Vol.34 (7), pp. 3663-3668. show abstract

Larkin, J., Fishman, M., Wood, L., Negrier, S., Olivier, K., Pyle, L., Gorbunova, V., Jonasch, E., Andrews, L. & Staehler, M., et al. (2014). Axitinib for the treatment of metastatic renal cell carcinoma: recommendations for therapy management to optimize outcomes. Am j clin oncol, Vol.37 (4), pp. 397-403. show abstract

Nobbenhuis, M.A., Lalondrelle, S., Larkin, J. & Banerjee, S. (2014). Management of melanomas of the gynaecological tract. Curr opin oncol, Vol.26 (5), pp. 508-513. show abstract

Furney, S.J., Turajlic, S., Stamp, G., Thomas, J.M., Hayes, A., Strauss, D., Gavrielides, M., Xing, W., Gore, M., Larkin, J., et al. (2014). The mutational burden of acral melanoma revealed by whole-genome sequencing and comparative analysis. Pigment cell & melanoma research, Vol.27 (5), pp. 835-838.

Coupe, N., Corrie, P., Hategan, M., Larkin, J., Gore, M.E., Gupta, A., Wise, A., Suter, S., Ciria, C., Love, S., et al. (2014). 1094PDA PHASE 1, DOSE ESCALATION STUDY OF PACLITAXEL WITH GSK1120212 (TRAMETINIB) FOR THE TREATMENT OF ADVANCED MELANOMA. Annals of oncology, Vol.25 (suppl_4), pp. iv379-iv379.

Schadendorf, D., Amonkar, M.M., Stroyakovskiy, D., Levchenko, E., Gogas, H., De Braud, F.G., Grob, J., Bondarenko, I., Garbe, C., Lebbe, C., et al. (2014). 1091PDCOMBI-D: QUALITY OF LIFE (QOL) IMPACT OF THE COMBINATION OF DABRAFENIB AND TRAMETINIB (D + T) VERSUS DABRAFENIB MONOTHERAPY (D) IN PATIENTS WITH BRAF V600E/K UNRESECTABLE OR METASTATIC MELANOMA IN A PHASE III TRIAL. Annals of oncology, Vol.25 (suppl_4), pp. iv377-iv377.

Gravis, G., Chanez, B., Derosa, L., Beuselinck, B., Laguerre, B., Barthelemy, P., Brachet, P.E., Lobbedez, F.J., Escudier, B., Stewart, G.D., et al. (2014). 825PIMPACT ON OVERALL SURVIVAL OF GLANDULAR METASTASIS IN PATIENTS WITH METASTATIC CLEAR CELL RENAL CELL CARCINOMA ON BEHALF OF THE RENAL CROSS CHANNEL GROUP. Annals of oncology, Vol.25 (suppl_4), pp. iv286-iv287.

Larkin, J. & Okines, A. (2014). 43INPRECISION MEDICINE IN KIDNEY CANCER AND CLINICAL TRIAL DESIGNS. Annals of oncology, Vol.25 (suppl_4), pp. iv17-iv17.

Leijen, S., Barlesi, F., Eberhardt, W.E., Martinez, G.M., Dieras, V., Schellens, J.H., Middleton, M., Calvo, E., Paz-Ares, L., Larkin, J., et al. (2014). OCULAR TOXICITIES OBSERVED WITH MEK INHIBITOR RO4987655 (CH4987655) IN A SINGLE AGENT PHASE I STUDY WITH EXTENSION IN PATIENTS WITH ADVANCED SOLID TUMORS. British journal of clinical pharmacology, Vol.78 (4), pp. 769-769.

Thian, Y., Gutzeit, A., Koh, D.-., Fisher, R., Lote, H., Larkin, J. & Sohaib, A. (2014). Revised Choi imaging criteria correlate with clinical outcomes in patients with metastatic renal cell carcinoma treated with sunitinib. Radiology, Vol.273 (2), pp. 452-461. show abstract

PURPOSE: To compare revised Choi criteria that incorporate concurrent size and attenuation changes at early follow-up imaging with Response Evaluation Criteria in Solid Tumors ( RECIST Response Evaluation Criteria in Solid Tumors ) 1.1 and original Choi criteria in stratification of clinical outcomes in patients with metastatic renal cell carcinoma ( mRCC metastatic renal cell carcinoma ) treated with sunitinib. MATERIALS AND METHODS: Institutional review board approved this retrospective study and waived informed consent. Baseline and first follow-up computed tomographic scans in 69 patients (50 men, 19 women; mean age, 60.3 years; range, 19-83 years) with mRCC metastatic renal cell carcinoma treated with sunitinib from October 1, 2008, to March 1, 2013, were evaluated for tumor response by using RECIST Response Evaluation Criteria in Solid Tumors 1.1, original Choi criteria, and revised Choi criteria. Correlations with overall survival ( OS overall survival ) and progression-free survival ( PFS progression-free survival ) were compared and stratified according to each radiologic criteria with Kaplan-Meier and multivariate Cox regression analysis. RESULTS: Median follow-up time was 29.7 months (95% confidence interval [ CI confidence interval ]: 18.9, 45.9). Response according to revised Choi criteria was independently correlated with OS overall survival (hazard ratio, 0.47 [95% CI confidence interval : 0.23, 0.99]; P = .046) and PFS progression-free survival (hazard ratio, 0.53 [95% CI confidence interval : 0.29, 0.99]; P = .047). Response according to RECIST Response Evaluation Criteria in Solid Tumors was not significantly correlated with OS overall survival (hazard ratio, 0.65 [95% CI confidence interval : 0.27, 1.58]; P = .344) or PFS progression-free survival (hazard ratio, 0.89 [95% CI confidence interval : 0.42, 1.91]; P = .768). Response according to original Choi criteria was not significantly correlated with OS overall survival (hazard ratio, 0.60 [95% CI confidence interval : 0.32, 1.11]; P = .106) or PFS progression-free survival (hazard ratio, 0.59 [95% CI confidence interval : 0.34, 1.02]; P = .060). Median OS overall survival and PFS progression-free survival in responders according to revised Choi criteria was 39.4 months (95% CI confidence interval : 9.1, upper limit not estimated) and 13.7 months (95% CI confidence interval : 6.4, 24.6), respectively, compared with 12.8 months (95% CI confidence interval : 8.7, 18.0) and 5.3 months (95% CI confidence interval : 3.9, 8.4), respectively, in nonresponders. CONCLUSION: Contemporaneous reduction in tumor size and attenuation were correlated with favorable clinical outcomes. Response according to revised Choi criteria showed better correlation with clinical outcomes compared with that according to RECIST Response Evaluation Criteria in Solid Tumors or original Choi criteria in patients with mRCC metastatic renal cell carcinoma treated with sunitinib..

Kenny, L.M., Tomasi, G., Turkheimer, F., Larkin, J., Gore, M., Brock, C.S., Mangar, S. & Aboagye, E.O. (2014). Preliminary clinical assessment of the relationship between tumor alphavbeta3 integrin and perfusion in patients studied with [18F]fluciclatide kinetics and [15O]H2O PET. Ejnmmi research, Vol.4 (1).

Larkin, J., Ascierto, P.A., Dréno, B., Atkinson, V., Liszkay, G., Maio, M., Mandalà, M., Demidov, L., Stroyakovskiy, D., Thomas, L., et al. (2014). Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N engl j med, Vol.371 (20), pp. 1867-1876. show abstract

BACKGROUND: The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. METHODS: We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. RESULTS: The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. CONCLUSIONS: The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.)..

Long, G.V., Stroyakovskiy, D., Gogas, H., Levchenko, E., de Braud, F., Larkin, J., Garbe, C., Jouary, T., Hauschild, A., Grob, J.J., et al. (2014). Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. New england journal of medicine, Vol.371 (20), pp. 1877-1888.

Zimmer, L., Barlesi, F., Martinez-Garcia, M., Dieras, V., Schellens, J.H., Spano, J.-., Middleton, M.R., Calvo, E., Paz-Ares, L., Larkin, J., et al. (2014). Phase I expansion and pharmacodynamic study of the oral MEK inhibitor RO4987655 (CH4987655) in selected patients with advanced cancer with RAS-RAF mutations. Clin cancer res, Vol.20 (16), pp. 4251-4261. show abstract

PURPOSE: This phase I expansion study assessed safety, pharmacodynamic effects, and antitumor activity of RO4987655, a pure MEK inhibitor, in selected patients with advanced solid tumor. EXPERIMENTAL DESIGN: We undertook a multicenter phase I two-part study (dose escalation and cohort expansion). Here, we present the part 2 expansion that included melanoma, non-small cell lung cancer (NSCLC), and colorectal cancer with oral RO4987655 administered continuously at recommended doses of 8.5 mg twice daily until progressive disease (PD). Sequential tumor sampling investigated multiple markers of pathway activation/tumor effects, including ERK phosphorylation and Ki-67 expression. BRAF and KRAS testing were implemented as selection criteria and broader tumor mutational analysis added. RESULTS: Ninety-five patients received RO4987655, including 18 BRAF-mutant melanoma, 23 BRAF wild-type melanoma, 24 KRAS-mutant NSCLC, and 30 KRAS-mutant colorectal cancer. Most frequent adverse events were rash, acneiform dermatitis, and gastrointestinal disorders, mostly grade 1/2. Four (24%) of 17 BRAF-mutated melanoma had partial response as did four (20%) of 20 BRAF wild-type melanoma and two (11%) of 18 KRAS-mutant NSCLC. All KRAS-mutant colorectal cancer developed PD. Paired tumor biopsies demonstrated reduced ERK phosphorylation among all cohorts but significant differences among cohorts in Ki-67 modulation. Sixty-nine percent showed a decrease in fluorodeoxyglucose uptake between baseline and day 15. Detailed mutational profiling confirmed RAS/RAF screening and identified additional aberrations (NRAS/non-BRAF melanomas; PIK3CA/KRAS colorectal cancer) without therapeutic implications. CONCLUSIONS: Safety profile of RO4987655 was comparable with other MEK inhibitors. Single-agent activity was observed in all entities except colorectal cancer. Evidence of target modulation and early biologic activity was shown among all indications independent of mutational status. Clin Cancer Res; 20(16); 4251-61. ©2014 AACR..

Antonia, S.J., Larkin, J. & Ascierto, P.A. (2014). Immuno-oncology combinations: a review of clinical experience and future prospects. Clin cancer res, Vol.20 (24), pp. 6258-6268. show abstract

Sanchez-Laorden, B., Viros, A., Girotti, M.R., Pedersen, M., Saturno, G., Zambon, A., Niculescu-Duvaz, D., Turajlic, S., Hayes, A., Gore, M., et al. (2014). BRAF Inhibitors Induce Metastasis in RAS Mutant or Inhibitor-Resistant Melanoma Cells By Reactivating MEK and ERK Signaling. Science signaling, Vol.7 (318).

Fisher, R., Horswell, S., Rowan, A., Salm, M.P., de Bruin, E.C., Gulati, S., McGranahan, N., Stares, M., Gerlinger, M., Varela, I., et al. (2014). Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution. Genome biology: biology for the post-genomic era, Vol.15 (8). show abstract

Ascierto, P.A., Grimaldi, A.M., Anderson, A.C., Bifulco, C., Cochran, A., Garbe, C., Eggermont, A.M., Faries, M., Ferrone, S., Gershenwald, J.E., et al. (2014). Future perspectives in melanoma research: meeting report from the "Melanoma Bridge", Napoli, December 5th-8th 2013. Journal of translational medicine, Vol.12.

Khattak, M.A., Bakr, F., Krzystanek, M., Szallasi, Z., Gerlinger, M., Santos, C., Swanton, C., Pickering, L.M., Gore, M.E. & Larkin, J.M., et al. (2013). Prognostic and predictive markers in metastatic renal cell carcinoma. J clin oncol, Vol.31 (7), pp. 971-972.

Larkin, J., Paine, A., Tumur, I., Cappelleri, J.C., Healey, P.J., Foley, G., Mitchell, S., Kroes, M. & Chen, C. (2013). Second-line treatments for the management of advanced renal cell carcinoma: systematic review and meta-analysis. Expert opin pharmacother, Vol.14 (1), pp. 27-39. show abstract

Sinha, R., Edmonds, K., Newton-Bishop, J., Gore, M., Larkin, J. & Fearfield, L. (2013). Erythema Nodosum-Like Panniculitis in Patients With Melanoma Treated With Vemurafenib. Journal of clinical oncology, Vol.31 (19), pp. E320-E321.

Khattak, M.A., Fisher, R., Hughes, P., Gore, M. & Larkin, J. (2013). Ipilimumab activity in advanced uveal melanoma. Melanoma res, Vol.23 (1), pp. 79-81. show abstract

Fisher, R., Gore, M. & Larkin, J. (2013). Current and future systemic treatments for renal cell carcinoma. Semin cancer biol, Vol.23 (1), pp. 38-45. show abstract

Girotti, M.R., Pedersen, M., Sanchez-Laorden, B., Viros, A., Turajlic, S., Niculescu-Duvaz, D., Zambon, A., Sinclair, J., Hayes, A., Gore, M., et al. (2013). Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer discov, Vol.3 (2), pp. 158-167. show abstract

Khattak, M., Fisher, R., Turajlic, S. & Larkin, J. (2013). Targeted therapy and immunotherapy in advanced melanoma: an evolving paradigm. Ther adv med oncol, Vol.5 (2), pp. 105-118. show abstract

Ascierto, P.A., Grimaldi, A.M., Acquavella, N., Borgognoni, L., Calabro, L., Cascinelli, N., Cesano, A., Del Vecchio, M., Eggermont, A.M., Faries, M., et al. (2013). Future perspectives in melanoma research Meeting report from the "Melanoma Bridge Napoli, December 2nd-4th 2012". Journal of translational medicine, Vol.11.

Fearfield, L., Newton-Bishop, J.A., Sinha, R., Edmonds, K., Gore, M.E. & Larkin, J. (2013). Second primary melanomas on treatment with vemurafenib: reply from the authors. Br j dermatol, Vol.168 (4), pp. 888-889.

Turajlic, S., Ali, Z., Yousaf, N. & Larkin, J. (2013). Phase I/II RAF kinase inhibitors in cancer therapy. Expert opin investig drugs, Vol.22 (6), pp. 739-749. show abstract

Furney, S.J., Turajlic, S., Stamp, G., Nohadani, M., Carlisle, A., Thomas, J.M., Hayes, A., Strauss, D., Gore, M., van den Oord, J., et al. (2013). Genome sequencing of mucosal melanomas reveals that they are driven by distinct mechanisms from cutaneous melanoma. J pathol, Vol.230 (3), pp. 261-269. show abstract

Martinez, P., Birkbak, N.J., Gerlinger, M., McGranahan, N., Burrell, R.A., Rowan, A.J., Joshi, T., Fisher, R., Larkin, J., Szallasi, Z., et al. (2013). Parallel evolution of tumour subclones mimics diversity between tumours. J pathol, Vol.230 (4), pp. 356-364. show abstract

Fisher, R. & Larkin, J. (2013). Individualising treatment choices in a crowded treatment algorithm. European journal of cancer supplements, Vol.11 (2), pp. 160-168.

Ali, Z., Yousaf, N. & Larkin, J. (2013). Melanoma epidemiology, biology and prognosis. European journal of cancer supplements, Vol.11 (2), pp. 81-91.

Yousaf, N. & Larkin, J. (2013). Axitinib in advanced renal-cell carcinoma. Lancet oncol, Vol.14 (13), pp. 1245-1246.

Gerlinger, M., Quezada, S.A., Peggs, K.S., Furness, A.J., Fisher, R., Marafioti, T., Shende, V.H., McGranahan, N., Rowan, A.J., Hazell, S., et al. (2013). Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. J pathol, Vol.231 (4), pp. 424-432. show abstract

Henrion, M., Frampton, M., Scelo, G., Purdue, M., Ye, Y., Broderick, P., Ritchie, A., Kaplan, R., Meade, A., McKay, J., et al. (2013). Common variation at 2q22 3 (ZEB2) influences the risk of renal cancer. Hum mol genet, Vol.22 (4), pp. 825-831. show abstract

Henrion, M., Frampton, M., Scelo, G., Purdue, M., Ye, Y., Broderick, P., Ritchie, A., Kaplan, R., Meade, A., McKay, J., et al. (2013). Common variation at 2q22 3 (ZEB2) influences the risk of renal cancer. Human molecular genetics, Vol.22 (10), pp. 2128-2128.

Vasudev, N.S., Goh, V., Juttla, J.K., Thompson, V.L., Larkin, J.M., Gore, M., Nathan, P.D. & Reynolds, A.R. (2013). Changes in tumour vessel density upon treatment with anti-angiogenic agents: relationship with response and resistance to therapy. British journal of cancer, Vol.109 (5).

Karapanagiotou, E.M., Roulstone, V., Twigger, K., Ball, M., Tanay, M., Nutting, C., Newbold, K., Gore, M.E., Larkin, J., Syrigos, K.N., et al. (2012). Phase I/II trial of carboplatin and paclitaxel chemotherapy in combination with intravenous oncolytic reovirus in patients with advanced malignancies. Clin cancer res, Vol.18 (7), pp. 2080-2089. show abstract

Pacey, S., Gore, M., Chao, D., Banerji, U., Larkin, J., Sarker, S., Owen, K., Asad, Y., Raynaud, F., Walton, M., et al. (2012). A Phase II trial of 17-allylamino, 17-demethoxygeldanamycin (17-AAG, tanespimycin) in patients with metastatic melanoma. Invest new drugs, Vol.30 (1), pp. 341-349. show abstract

Fisher, R., Cahalin, P., Gore, M. & Larkin, J. (2012). A tale of two tumours and a plea for progress. Lancet oncol, Vol.13 (2), pp. 124-125.

Turajlic, S., Furney, S.J., Lambros, M.B., Mitsopoulos, C., Kozarewa, I., Geyer, F.C., Mackay, A., Hakas, J., Zvelebil, M., Lord, C.J., et al. (2012). Whole genome sequencing of matched primary and metastatic acral melanomas. Genome res, Vol.22 (2), pp. 196-207. show abstract

Gruenwald, V., Karakiewicz, P.I., Bavbek, S.E., Miller, K., Machiels, J.-., Lee, S.-., Larkin, J., Bono, P., Rha, S.Y., Castellano, D., et al. (2012). An international expanded-access programme of everolimus: Addressing safety and efficacy in patients with metastatic renal cell carcinoma who progress after initial vascular endothelial growth factor receptor-tyrosine kinase inhibitor therapy. European journal of cancer, Vol.48 (3), pp. 324-332.

Fisher, R. & Larkin, J. (2012). Treatment of brain metastases in patients with melanoma. Lancet oncol, Vol.13 (5), pp. 434-435.

Young, K., Minchom, A. & Larkin, J. (2012). BRIM-1, -2 and -3 trials: improved survival with vemurafenib in metastatic melanoma patients with a BRAF(V600E) mutation. Future oncol, Vol.8 (5), pp. 499-507. show abstract

Gerlinger, M., Santos, C.R., Spencer-Dene, B., Martinez, P., Endesfelder, D., Burrell, R.A., Vetter, M., Jiang, M., Saunders, R.E., Kelly, G., et al. (2012). Genome-wide RNA interference analysis of renal carcinoma survival regulators identifies MCT4 as a Warburg effect metabolic target. J pathol, Vol.227 (2), pp. 146-156. show abstract

Larkin, J., Esser, N., Calvo, E., Tsuchihashi, Z., Fiedler, U., Graeser, R. & Kim, D. (2012). Efficacy of sequential treatment with sunitinib-everolimus in an orthotopic mouse model of renal cell carcinoma. Anticancer res, Vol.32 (7), pp. 2399-2406. show abstract

Gerlinger, M., Rowan, A.J., Horswell, S., Math, M., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., et al. (2012). Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N engl j med, Vol.366 (10), pp. 883-892. show abstract

BACKGROUND: Intratumor heterogeneity may foster tumor evolution and adaptation and hinder personalized-medicine strategies that depend on results from single tumor-biopsy samples. METHODS: To examine intratumor heterogeneity, we performed exome sequencing, chromosome aberration analysis, and ploidy profiling on multiple spatially separated samples obtained from primary renal carcinomas and associated metastatic sites. We characterized the consequences of intratumor heterogeneity using immunohistochemical analysis, mutation functional analysis, and profiling of messenger RNA expression. RESULTS: Phylogenetic reconstruction revealed branched evolutionary tumor growth, with 63 to 69% of all somatic mutations not detectable across every tumor region. Intratumor heterogeneity was observed for a mutation within an autoinhibitory domain of the mammalian target of rapamycin (mTOR) kinase, correlating with S6 and 4EBP phosphorylation in vivo and constitutive activation of mTOR kinase activity in vitro. Mutational intratumor heterogeneity was seen for multiple tumor-suppressor genes converging on loss of function; SETD2, PTEN, and KDM5C underwent multiple distinct and spatially separated inactivating mutations within a single tumor, suggesting convergent phenotypic evolution. Gene-expression signatures of good and poor prognosis were detected in different regions of the same tumor. Allelic composition and ploidy profiling analysis revealed extensive intratumor heterogeneity, with 26 of 30 tumor samples from four tumors harboring divergent allelic-imbalance profiles and with ploidy heterogeneity in two of four tumors. CONCLUSIONS: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development. Intratumor heterogeneity, associated with heterogeneous protein function, may foster tumor adaptation and therapeutic failure through Darwinian selection. (Funded by the Medical Research Council and others.)..

Khattak, M., Gore, M., Larkin, J., Strauss, D., Thomas, M., Hayes, A. & Harrington, K. (2012). Adjuvant nodal irradiation in melanoma. Lancet oncol, Vol.13 (8), pp. e326-e327.

Larkin, J.M., Fisher, R.A. & Gore, M.E. (2012). Adjuvant Interferon Therapy for Patients at High Risk for Recurrent Melanoma: An Updated Systematic Review. Clinical oncology, Vol.24 (6), pp. 410-412.

Thway, K., du Parcq, J., Larkin, J.M., Fisher, C. & Livni, N. (2012). Metastatic renal mucinous tubular and spindle cell carcinoma Atypical behavior of a rare, morphologically bland tumor. Ann diagn pathol, Vol.16 (5), pp. 407-410. show abstract

Larkin, J.M., Blank, C.U., Bono, P., Gogov, S., Panneerselvam, A., Garay, C.A., Gruenwald, V. & Grp, R.E. (2012). Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy. Journal of clinical oncology, Vol.30 (5).

Blank, C.U., Bono, P., Larkin, J.M., Gogov, S., Panneerselvam, A., Garay, C.A., Gruenwald, V. & Grp, R.E. (2012). Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT. Journal of clinical oncology, Vol.30 (5).

Larkin, J.M., Blank, C.U., Bono, P., Gogov, S., Panneerselvam, A., Garay, C.A., Grünwald, V. & REACT Study Group, (2012). Everolimus in patients with metastatic renal cell carcinoma refractory to VEGF-targeted therapy: REACT subgroup analysis of prior therapy. J clin oncol, Vol.30 (5_suppl), p. 391. show abstract

Blank, C.U., Bono, P., Larkin, J.M., Gogov, S., Panneerselvam, A., Garay, C.A., Grünwald, V. & REACT Study Group, (2012). Safety and efficacy of everolimus in patients with non-clear cell renal cell carcinoma refractory to VEGF-targeted therapy: Subgroup analysis of REACT. J clin oncol, Vol.30 (5_suppl), p. 402. show abstract

402 Background: Metastatic non-clear cell renal cell carcinoma (mncRCC), which accounts for about 25% of all RCCs, is characterized by resistance to treatment and poor overall survival. Despite recent advances in targeted therapies for patients with mRCC, effective therapies for patients with mncRCC remain limited. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated to provide patients with mRCC of any histology refractory to VEGF-targeted therapy access to everolimus in advance of regulatory approval. METHODS: REACT, an open-label, international, expanded-access program (Clinicaltrials.gov: NCT00655252 ) enrolled patients with measurable or nonmeasurable mRCC of any histology who were intolerant of, or progressed while on, VEGFR-TKI therapy in order to evaluate the long-term safety of everolimus 10 mg daily. Overall incidence of grade 3/4 and serious adverse events (AEs) were recorded, as was tumor response to everolimus according to RECIST criteria. A subgroup analysis of safety and efficacy in patients with mncRCC was performed. RESULTS: Of 1367 patients enrolled, 75 patients (5.5%) had mncRCC. Median everolimus treatment duration in the mncRCC subgroup was 12.14 weeks (range, 0.9-49.0 weeks) and in the overall REACT population it was 14.0 weeks (range, 0.1-83.7 weeks). In the mncRCC subgroup, most commonly reported grade 3/4 AEs were anemia (17.3%), dyspnea (10.7%), pleural effusion (9.3%), fatigue (8.0%), and hyperglycemia (6.6%). Best overall response was similar in the mncRCC subgroup and overall population: respectively, 1.3% and 1.7% had partial response and 49.3% and 51.6% had stable disease. CONCLUSIONS: Although patients with mncRCC had a slightly lower treatment duration than the overall REACT population, approximately 50% of these patients achieved disease control on treatment. In this subgroup, everolimus was well tolerated, no new safety issues were observed, and the AE profile was consistent with that of the overall population. These encouraging results of the safety and efficacy of everolimus in patients with mncRCC support further evaluation of everolimus in these patients..

Khattak, M.A., Fisher, R.A., Pickering, L.M., Gore, M.E. & Larkin, J.M. (2012). Endobronchial metastases from renal cell carcinoma: a late manifestation of the disease with an increasing incidence. Bju int, Vol.110 (10), pp. 1407-1408.

Sinha, R., Edmonds, K., Newton-Bishop, J.A., Gore, M.E., Larkin, J. & Fearfield, L. (2012). Cutaneous adverse events associated with vemurafenib in patients with metastatic melanoma: practical advice on diagnosis, prevention and management of the main treatment-related skin toxicities. Br j dermatol, Vol.167 (5), pp. 987-994. show abstract

Proskorovsky, I., Benedict, A., Larkin, J.M., Sandin, R. & Chen, C. (2012). AXITINIB (AXI) AND BEST SUPPORTIVE CARE (BSC) IN THE TREATMENT OF SUNITINIB-REFRACTORY PATIENTS WITH METASTATIC RENAL CELL CARCINOMA (MRCC): RESULTS OF A SIMULATED TREATMENT COMPARISON (STC) ANALYSES. Value in health, Vol.15 (7), pp. A410-A410.

Flaherty, K.T., Robert, C., Hersey, P., Nathan, P., Garbe, C., Milhem, M., Demidov, L.V., Hassel, J.C., Rutkowski, P., Mohr, P., et al. (2012). Improved Survival with MEK Inhibition in BRAF-Mutated Melanoma. New england journal of medicine, Vol.367 (2), pp. 107-114.

Kirkwood, J.M., Bastholt, L., Robert, C., Sosman, J., Larkin, J., Hersey, P., Middleton, M., Cantarini, M., Zazulina, V., Kemsley, K., et al. (2012). Phase II, Open-Label, Randomized Trial of the MEK1/2 Inhibitor Selumetinib as Monotherapy versus Temozolomide in Patients with Advanced Melanoma. Clinical cancer research, Vol.18 (2), pp. 555-567.

Gerlinger, M., Rowan, A., Horswell, S., Larkin, J., Endesfelder, D., Gronroos, E., Martinez, P., Matthews, N., Stewart, A., Tarpey, P., et al. (2012). Abstract 964: Intra-tumor heterogeneity and Darwinian selection revealed by multi-region exome sequencing of renal cell carcinomas. Clinical research, .

Larkin, J., Goh, X.Y., Vetter, M., Pickering, L. & Swanton, C. (2012). Epigenetic regulation in RCC: opportunities for therapeutic intervention?. Nat rev urol, Vol.9 (3), pp. 147-155. show abstract

Swanton, C., Larkin, J. & Gerlinger, M. (2012). Intratumor Heterogeneity and Branched Evolution REPLY. New england journal of medicine, Vol.366 (22), pp. 2133-2133.

Fisher, R., Pender, A., Thillai, K., Chowdhury, S., Pickering, L., Khabra, K., Gore, M. & Larkin, J. (2012). Observation as a treatment strategy for advanced renal cell carcinoma-a call for prospective validation. Front oncol, Vol.2, p. 155.

Fisher, R. & Larkin, J. (2012). Vemurafenib: a new treatment for BRAF-V600 mutated advanced melanoma. Cancer manag res, Vol.4, pp. 243-252. show abstract

Fisher, R., Larkin, J. & Swanton, C. (2012). Inter and intratumour heterogeneity: a barrier to individualized medical therapy in renal cell carcinoma?. Front oncol, Vol.2, p. 49.

Suwaki, N., Vanhecke, E., Atkins, K.M., Graf, M., Swabey, K., Huang, P., Schraml, P., Moch, H., Cassidy, A.M., Brewer, D., et al. (2011). A HIF-regulated VHL-PTP1B-Src signaling axis identifies a therapeutic target in renal cell carcinoma. Sci transl med, Vol.3 (85), p. 85ra47. show abstract

Gore, M.E. & Larkin, J.M. (2011). Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies. British journal of cancer, Vol.104 (3), pp. 399-406.

Khan, O.A., Gore, M., Lorigan, P., Stone, J., Greystoke, A., Burke, W., Carmichael, J., Watson, A.J., McGown, G., Thorncroft, M., et al. (2011). A phase I study of the safety and tolerability of olaparib (AZD2281, KU0059436) and dacarbazine in patients with advanced solid tumours. British journal of cancer, Vol.104 (5), pp. 750-755.

Okera, M., Chan, S., Dernede, U., Larkin, J., Popat, S., Gilbert, D., Jones, L., Osuji, N., Sykes, H., Oakley, C., et al. (2011). A prospective study of chemotherapy-induced febrile neutropenia in the South West London Cancer Network Interpretation of study results in light of NCAG/NCEPOD findings. British journal of cancer, Vol.104 (3), pp. 407-412.

Larkin, J., Swanton, C. & Pickering, L. (2011). Optimizing treatment of metastatic renal cell carcinoma by changing mechanism of action. Expert rev anticancer ther, Vol.11 (4), pp. 639-649. show abstract

Bex, A., Larkin, J. & Blank, C. (2011). Non-Clear Cell Renal Cell Carcinoma: How New Biological Insight May Lead to New Therapeutic Modalities. Current oncology reports, Vol.13 (3), pp. 240-248.

Fisher, R., Pickering, L. & Larkin, J. (2011). New targeted therapies for renal cell carcinoma. Expert opin investig drugs, Vol.20 (7), pp. 933-945. show abstract

Josephs, D., Hutson, T.E., Cowey, C.L., Pickering, L.M., Larkin, J.M., Gore, M.E., Van Hemelrijck, M., McDermott, D.F., Powles, T., Chowdhury, P., et al. (2011). Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma with severe renal impairment or on haemodialysis. Bju international, Vol.108 (8), pp. 1279-1283.

Larkin, J.M. & Gore, M.E. (2011). Primary Excision Margins and Sentinel Lymph Node Biopsy in Clinically Node-negative Melanoma of the Trunk or Extremities. Clinical oncology, Vol.23 (9), pp. 569-571.

Minchom, A., Young, K. & Larkin, J. (2011). Ipilimumab: showing survival benefit in metastatic melanoma. Future oncol, Vol.7 (11), pp. 1255-1264. show abstract

Sanz-Moreno, V., Gaggioli, C., Yeo, M., Albrengues, J., Wallberg, F., Viros, A., Hooper, S., Mitter, R., Féral, C.C., Cook, M., et al. (2011). ROCK and JAK1 signaling cooperate to control actomyosin contractility in tumor cells and stroma. Cancer cell, Vol.20 (2), pp. 229-245. show abstract

Larkin, J.M., Fisher, R.A., Pickering, L.M., Sohaib, S.A., Ghosn, M., Christmas, T., Cordiner, R.L. & Gore, M.E. (2011). Chromophobe Renal Cell Carcinoma With Prolonged Response to Sequential Sunitinib and Everolimus. Journal of clinical oncology, Vol.29 (9), pp. E241-E242.

Chapman, P.B., Hauschild, A., Robert, C., Larkin, J.M., Haanen, J.B., Ribas, A., Hogg, D., O'Day, S., Ascierto, P.A., Testori, A., et al. (2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with (V600E)BRAF-mutated melanoma. Journal of clinical oncology, Vol.29 (18).

Ratnayake, G., Pender, A., Pickering, L.M., Gore, M.E. & Larkin, J.M. (2011). Intrapatient correlation of clinical benefit from VEGF and mTOR inhibition in metastatic renal cell carcinoma. Journal of clinical oncology, Vol.29 (15).

Hutson, T.E., Bukowski, R.M., Rini, B.I., Gore, M.E., Larkin, J.M., Figlin, R.A., Barrios, C.H., Escudier, B., Lin, X., Fly, K.D., et al. (2011). A pooled analysis of the efficacy and safety of sunitinib in elderly patients (pts) with metastatic renal cell carcinoma (mRCC). Journal of clinical oncology, Vol.29 (15).

Leary, A., Pickering, L.M., Larkin, J.M., Leach, M.O., Gore, M.E., Sohaib, A., Collins, D.J. & Koh, D. (2011). Quantitative diffusion-weighted (DW) MR imaging of microcapillary perfusion and tissue diffusivity as biomarkers of response of renal cell carcinoma (RCC) to treatment with sunitinib. Journal of clinical oncology, Vol.29 (15).

Fisher, R.A., Pender, A., Thillai, K., Chowdhury, S., Pickering, L.M., Rose, S.S., Gore, M.E. & Larkin, J.M. (2011). Observation prior to systemic therapy in patients with metastatic renal cell carcinoma in the kinase inhibitor era. Journal of clinical oncology, Vol.29 (15).

Chapman, P.B., Hauschild, A., Robert, C., Larkin, J.M., Haanen, J.B., Ribas, A., Hogg, D., O'Day, S., Ascierto, P.A., Testori, A., et al. (2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas. Journal of clinical oncology, Vol.29 (15).

Gruenwald, V., Karakiewicz, P.I., Bavbek, S.E., Miller, K., Machiels, J.H., Lee, S., Larkin, J.M., Bono, P., Rha, S.Y., Castellano, D.E., et al. (2011). Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. Journal of clinical oncology, Vol.29 (15).

LBA4 Background: About 50% of melanomas have an activating (V600E)BRAF mutation which led to the hypothesis that inhibition of the mutated BRAF kinase may be of clinical benefit. Phase I and II trials with vemurafenib (previously PLX4032/RO5185426), an orally available inhibitor of oncogenic BRAF kinase, showed response rates (RR; CR+PR) >50% in (V600E)BRAF- mutated melanoma patients (pts). We conducted a phase III trial to determine if vemurafenib improved overall survival (OS) and progression-free survival (PFS) in melanoma pts with (V600E)BRAF mutation. METHODS: Pts with previously untreated, unresectable stage IIIC or stage IV melanoma that tested positive for (V600E)BRAF mutation by the cobas 4800 BRAF V600 Mutation Test were randomized (1:1) to vemurafenib (960 mg po bid) or DTIC (1,000 mg/m(2), IV, q3w). Randomization was stratified by PS, stage, LDH, and geographic region. Pts were assessed for tumor responses after weeks 6, 12, and then q9 weeks. Co-primary endpoints were OS and PFS on the intent-to-treat population; secondary endpoints included RR, response duration, and safety. Final analysis was planned at 196 deaths. RESULTS: 675 pts were enrolled at 103 centers worldwide between Jan and Dec 2010. Treatment cohorts were well-balanced. At the pre-planned interim analysis (50% of deaths needed for final analysis), the hazard ratios for OS and PFS were 0.37 (95% CI 0.26 to 0.55; p<0.0001) and 0.26 (95% CI 0.20 to 0.33; p<0.0001), respectively, both in favor of vemurafenib. The confirmed RR was 48.4% and 5.5% to vemurafenib and DTIC, respectively, among the 65% of pts evaluable for RR to date. Benefit in OS, PFS, and RR was seen in all subgroups examined. Due to these data, the DTIC cohort has been allowed to cross over to vemurafenib. At the time of data analysis, 66% of vemurafenib pts and 25% DTIC pts were still on treatment. The most common toxicities of vemurafenib were: diarrhea, rash, alopecia, photosensitivity, fatigue, arthralgia, and keratoacanthoma/skin squamous cell carcinoma. CONCLUSIONS: Vemurafenib is associated with significantly improved OS and PFS compared to DTIC in pts with previously untreated, (V600E)BRAF-mutated metastatic melanoma..

4604 Background: Sunitinib is approved multinationally for mRCC treatment (Tx), with demonstrated activity and tolerability in both the first- and second-line Tx settings. Here, we report a retrospective analysis of the efficacy and safety of sunitinib as a function of age in pts with mRCC from 6 clinical trials. METHODS: Analyses included pooled data from 1,059 pts who received single-agent sunitinib on the approved 50 mg/d 4-week-on/2-week-off schedule (n=689; 65%) or at 37.5 mg continuous once-daily dosing (n=370; 35%), in both the first- (n=783; 74%) and second-line (n=276; 26%) Tx settings. Median progression-free survival (PFS) and overall survival (OS) were estimated by Kaplan-Meier method and compared between pts <70 vs. ≥70 yrs of age by log-rank test. Adverse event (AE) rates were also compared. RESULTS: Of 1,059 pts, 857 (81%) were of age <70 yrs and 202 (19%) ≥70 yrs, with median ages of 57 and 73 yrs, respectively. 73% and 59% were male, but otherwise baseline characteristics were similar. Median PFS was similar in both groups (9.0 vs. 10.9 mo; HR, 0.85; 95% CI, 0.70-1.02; P=0.0830), as was median OS (23.3 vs. 23.7 mo; HR, 0.94; 95% CI, 0.76-1.15; P=0.5441). In addition, efficacy was similar by age regardless of Tx setting. In first-line pts <70 vs. ≥70 yrs, median PFS and OS were 9.9 mo (95% CI, 8.3-10.7) vs. 11.0 mo (95% CI, 9.0-14.7) and 23.5 mo (95% CI, 21.1-27.6) vs. 25.5 mo (95% CI, 21.6-38.4); in second-line pts, median PFS and OS were 8.1 mo (95% CI, 7.8-8.7) vs. 8.4 mo (95% CI, 6.3-14.2) and 20.1 mo (95% CI, 16.2-25.0) vs. 15.8 mo (95% CI, 13.7-23.9). Most Tx-emergent AEs occurred at similar rates in both age groups; however, some AEs were significantly less common in pts aged <70 vs. ≥70 yrs, including fatigue (59% vs. 69%), decreased appetite/weight (29% vs. 53%), cough (20% vs. 29%), peripheral edema (17% vs. 27%), anemia (17% vs. 25%), and thrombocytopenia (16% vs. 25%; all P<0.05). Hand-foot syndrome was more common in younger pts (32% vs. 24%; P<0.05). CONCLUSIONS: In pts with mRCC, the efficacy of sunitinib was comparable in the elderly population, deriving similar benefit as younger pts regardless of Tx setting. The AE profiles were also similar, although some AEs were more common in elderly pts..

Fisher, R.A., Pender, A., Thillai, K., Chowdhury, S., Pickering, L.M., St Rose, S., Gore, M.E. & Larkin, J.M. (2011). Observation prior to systemic therapy in patients with metastatic renal cell carcinoma in the kinase inhibitor era. J clin oncol, Vol.29 (15_suppl), p. 4630. show abstract

4630 Background: Patients with metastatic renal cell carcinoma (mRCC) are heterogenous, with significant variation in clinical course. The use of vascular endothelial growth factor receptor (VEGFR) and mammalian target of rapamycin (mTOR) kinase inhibitors has dramatically changed the prognosis for these patients. However, these treatments are non-curative, necessitating chronic therapy. There is a cohort of patients with indolent disease in whom the initiation of systemic therapy is often deferred. It is inferred that the planned deferment of systemic therapy does not negatively impact on clinical benefit, but there is a lack of published data in the 'kinase inhibitor era' to support this contention. METHODS: This was a retrospective study. Patients with mRCC treated with sunitinib who had a planned period of observation prior to the initiation of systemic therapy because of asymptomatic or slowly progressive disease were analysed. The primary objective was to determine the progression free survival (PFS) of patients on deferred first-line systemic therapy. RESULTS: Records of 251 patients treated with sunitinib between 2005 and 2010 were reviewed; 64 patients who met the criteria were identified. The median age at diagnosis was 56 years and 75% were male; 80% had clear cell mRCC. All patients but one had a favourable or intermediate prognosis (Heng). The median time from diagnosis of metastases to starting treatment was 14.7 months (95% CI 10.4-16.3) Initial systemic therapy was interferon for 28% of patients and sunitinib for 65% of patients. Interferon patients had a median PFS of 6.3 months (95% CI 3.3-9.9), and sunitinib patients had a median PFS of 4.3 months (95% CI 3.6-7.3). Patients who received a VEGFR kinase inhibitor as second-line therapy after interferon had a median PFS of 7 months (95% CI 4.3-12.5). The median overall survival for all patients was 35 months (95% CI 26-42.3). CONCLUSIONS: In this cohort of patients with indolent favourable or intermediate prognosis mRCC, systemic treatment was deferred by a median of over one year but the efficacy of delayed sunitinib treatment was less than expected. Further study is required to define the group of patients for whom delayed systemic therapy is optimal..

Larkin, J.M., Turajlic, S., Nathan, P.D., Lorigan, P., Stamp, G., Gonzalez de Castro, D., Martin, N., Griffiths, J., Edmonds, K., Sarker, S., et al. (2011). A phase II trial of nilotinib in the treatment of patients with KIT mutated advanced acral and mucosal melanoma (NICAM). J clin oncol, Vol.29 (15_suppl), p. TPS229. show abstract

TPS229 Background: Recent studies have indicated that KIT mutations occur in approximately 20% of acral and mucosal melanomas (Curtin, al. 2006; Beadling, et al. 2008). Several case reports have shown that KIT mutated melanomas can respond to treatment with KIT inhibitors (Hodi et al. 2008; Lutzky et al. 2008; Quintas-Cardama et al. 2008; Handolias et al. 2010; Itoh, et al. 2010; Satzger et al. 2010; Terheyden et al. 2010; Woodman and Davies 2010) suggesting that such tumours critically depend on upregulated KIT signalling. Nilotinib, which potently inhibits the tyrosine kinase activity of BCR-ABL and KIT, has been evaluated in patients with advanced KIT mutated GIST and has shown clinical efficacy at well tolerated doses (Demetri et al. 2009; Montemurro et al. 2009; Schlemmer et al. 2010). METHODS: NICAM is a single arm 2-stage open label phase II study of nilotinib in KIT mutated advanced mucosal or acral melanoma. Patients with KIT mutations known to confer resistance to nilotinib are excluded. The primary objective in this feasibility study is to evaluate the efficacy of nilotinib in KIT mutated advanced mucosal and acral melanoma with a primary endpoint of progression free survival at 6 months. Secondary endpoints include response rate at 12 weeks; overall survival; toxicity of treatment; correlation between the response to nilotinib and KIT genotype, KIT gene copy number and KIT expression. In addition, the following will be explored: 1. Suppression of phosphorylation of KIT and downstream pathways on day 15 tumour biopsies; 2. Possible mechanisms of resistance by analysis of biopsies obtained at disease progression; 3. The use of circulating tumour DNA for non-invasive KIT mutational testing; 4. Genetic lesions that potentially cooperate with oncogenic KIT in melanoma (using Next Generation Sequencing). All patients are treated until disease progression or unacceptable toxicity. If 2 or more of the first 9 patients are progression free at 6 months, patient entry will continue into the second stage until a total of 24 patients have been recruited. To date, 45 patients have been registered and screened for KIT mutation and 5 patients have entered the study..

TPS154 Background: The anti-angiogenic tyrosine kinase inhibitor, sunitinib has been shown to significantly improve progression-free (PFS) and overall survival in RCC (Motzer 2009). However assessing response by conventional imaging is inadequate as sunitinib can alter perfusion and induce necrosis with no change in tumor size (Jaffe 2006). DW-MRI measures the motion of water molecules using the apparent diffusion coefficient (ADC) to quantify tissue diffusivity (D), an indirect measure of tissue density. ADC values are low in viable tumor and increase with treatment-induced apoptosis or necrosis (Theony 2010). In addition, DW-MRI obtained using low diffusion weightings can measure tissue perfusion (f) (Theony 2010; Koh 2006). Therefore DW-MRI may provide an early marker of response to sunitinib in RCC by detecting both changes in perfusion (anti-angiogenic effect) and changes in tissue diffusivity (necrosis). METHODS: This is a single arm prospective study. Main inclusion criteria are metastatic clear cell RCC, eligible for first-line sunitinib and target lesion >2.5cm assessable by functional MRI. 30 patients will be enrolled and undergo DW-MRI at baseline and after 7 and 28 days of sunitinib. Two baseline DW-MRI are performed 1 day apart to assess reproducibility. Objective response will be assessed on CT after 12 weeks by RECIST and pts followed up for PFS. The primary endpoint is to determine whether DW-MRI can identify responders versus non-responders to sunitinib in RCC. Secondary endpoints include investigating whether quantitative measurement of diffusion and perfusion (ADC, D, f) by DW-MRI correlates with objective tumor response and PFS. For DW-MRI, targeted acquisition measurements will be made using up to 10b-values, ranging between 0 and 1000s/mm(2). Unenhanced T1- and T2-, DCE-MR imaging sequences will also be performed. Paired baseline measurements will be used to compute measurement reproducibility. Absolute and % change in ADC, D and f at 7 and 28 days will be compared to baseline, and the limits of baseline reproducibility (Bland-Altman Statistics) used to define whether biomarker change is significant..

e15175 Background: Sequential inhibition of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) signalling is the standard systemic therapy paradigm for metastatic renal cell carcinoma (mRCC). We investigated whether clinical benefit for mRCC patients treated with VEGF inhibitors (VEGFi) predicted clinical benefit from mTOR inhibitors (mTORi) in individual patients. METHODS: Data were analysed for mRCC patients treated with VEGFi and mTORi in either sequence. Median time on treatment (TT) for VEGFi and mTORi were compared using the Mann-Whitney U test, and Kendall's tau to assess correlation of VEGFi and mTORi TT for each patient. For patients treated with >1 VEGFi, TT for the 1(st) VEGFi was analysed. Patients were divided into 4 groups: TT of mTORi and VEGFi <6 and >6 months duration, comparing duration between groups with a log rank test. Modified Motzer Scores (mMS) at time of 1(st) VEGFi/mTORi for these 4 groups were calculated as surrogate markers for tumour biology. RESULTS: Thirty five patients received both mTORi and VEGFi to disease progression, of whom only 2 received mTORi before VEGFi. Seven patients were female, and median age at start of 1(st) VEGFi/mTORi was 58.9 years. The median TT for VEGFi and mTORi were 5.4 months (95% CI 2.2-8.6) and 6.9 months (95% CI 2.5-11.3) respectively, and not significantly different. Kendall tau intrapatient correlation coefficient for TT on mTORi and VEGFi was 0.069 (p=0.56), suggesting no significant correlation. The mean mMS for patients with TT on mTORi <6 vs >6 months were 2.00 and 1.89 (median 2 and 2) respectively (p=0.79), and 2.11 and 1.18 (median 2 and 1) respectively (p=0.00092) for TT on VEGFi. CONCLUSIONS: In this small retrospective analysis, there was no significant correlation within patients between TT for mTORi and VEGFi. The significantly lower mMS for patients on VEGFi with a TT >6 months vs <6 months is consistent with previous analyses by Heng and colleagues. No such significant difference was seen with mTORi, implying mMS may not have the same prognostic value. These associations require further study..

Chapman, P.B., Hauschild, A., Robert, C., Larkin, J.M., Haanen, J.B., Ribas, A., Hogg, D., O'Day, S., Ascierto, P.A., Testori, A., et al. (2011). Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor RG7204 with dacarbazine in patients with V600E BRAF-mutated melanomas. J clin oncol, Vol.29 (15_suppl), p. LBA4. show abstract

Grünwald, V., Karakiewicz, P.I., Bavbek, S.E., Miller, K., Machiels, J.H., Lee, S., Larkin, J.M., Bono, P., Rha, S.Y., Castellano, D.E., et al. (2011). Final results of the international, expanded-access program of everolimus in patients with advanced renal cell carcinoma who progress after prior vascular endothelial growth factor receptor-tyrosine kinase inhibitor (VEGFr-TKI) therapy. J clin oncol, Vol.29 (15_suppl), p. 4601. show abstract

4601 Background: The phase III RECORD-1 trial established everolimus as the only agent proven to benefit patients with metastatic renal cell carcinoma (mRCC) after failure of initial VEGFr-TKI therapy. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, more than doubled median progression-free survival compared with placebo, from 1.9 months to 4.9 months. The REACT (RAD001 Expanded Access Clinical Trial in RCC) study was initiated in order to address an unmet medical need and provide everolimus in advance of regulatory approval and commercial availability to patients with mRCC after failure of initial VEGFr-TKI therapy. METHODS: REACT was an open-label, international, expanded-access clinical trial (Clinicaltrials.gov: NCT00655252 ). Eligible patients had measurable or nonmeasurable mRCC of any histology, were intolerant of, or progressed while on, VEGFr-TKI therapy, had a Karnofsky performance score ≥70%, and had adequate bone marrow, hepatic, and renal function. Patients received everolimus 10 mg/day orally, with dose and schedule modifications allowed for toxicity. The primary objective of REACT was to evaluate the long-term safety of everolimus in patients with mRCC, as determined by the overall incidence of grade 3/4 and serious adverse events (AEs). Tumor response to everolimus was also assessed according to RECIST. RESULTS: A total of 1367 patients from 34 countries were enrolled. Safety findings and tumor responses were consistent with those observed in RECORD-1. The most commonly reported grade 3/4 AEs were anemia (13.4%), fatigue (6.7%), and dyspnea (6.4%), and the most frequent serious AEs were dyspnea (5.0%), pneumonia (4.7%), and anemia (4.1%). Median dose intensity was 10.0 mg/day; relative dose intensity ranged from 0.90 to 1.10 in 68.9% of patients. CONCLUSIONS: REACT evaluated the safety and tolerability of everolimus in a broader patient population than the controlled trial RECORD-1. Everolimus was well tolerated, with no new safety issues identified and infrequent dose reductions/interruptions in the majority of patients..

Chapman, P.B., Hauschild, A., Robert, C., Haanen, J.B., Ascierto, P., Larkin, J., Dummer, R., Garbe, C., Testori, A., Maio, M., et al. (2011). Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. New england journal of medicine, Vol.364 (26), pp. 2507-2516.

Fisher, R. & Larkin, J. (2011). Renal cell cancer: what can we learn from pre-operative studies?. Front oncol, Vol.1, p. 51.

Larkin, J., Fisher, R., Pickering, L., Thway, K., Livni, N., Fisher, C. & Gore, M. (2010). Metastatic Mucinous Tubular and Spindle Cell Carcinoma of the Kidney Responding to Sunitinib. J clin oncol, Vol.28 (28), pp. E539-E540.

Rennalls, L.P., Seidl, T., Larkin, J.M., Wellbrock, C., Gore, M.E., Eisen, T. & Bruno, L. (2010). The melanocortin receptor agonist NDP-MSH impairs the allostimulatory function of dendritic cells. Immunology, Vol.129 (4), pp. 610-619.

Mukherji, D., Larkin, J. & Pickering, L. (2010). Sunitinib for metastatic renal cell carcinoma. Future oncology, Vol.6 (9), pp. 1377-1385.

Goldstein, R., Pickering, L. & Larkin, J. (2010). Does axitinib (AG-01376) have a future role in metastatic renal cell carcinoma and other malignancies?. Expert review of anticancer therapy, Vol.10 (10), pp. 1545-1557.

Larkin, J.M., Ferguson, T.R., Pickering, L.M., Edmonds, K., James, M.G., Thomas, K., Banerji, U., Berns, B., de Boer, C. & Gore, M.E., et al. (2010). A phase I/II trial of sorafenib and infliximab in advanced renal cell carcinoma. Br j cancer, Vol.103 (8), pp. 1149-1153. show abstract

BACKGROUND: There is clinical evidence to suggest that tumour necrosis factor-α (TNF-α) may be a therapeutic target in renal cell carcinoma (RCC). Multi-targeted kinase inhibitors, such as sorafenib and sunitinib, have become standard of care in advanced RCC. The anti-TNF-α monoclonal antibody infliximab and sorafenib have differing cellular mechanisms of action. We conducted a phase I/II trial to determine the safety and efficacy of infliximab in combination with sorafenib in patients with advanced RCC. METHODS: Eligible patients were systemic treatment-naive or had received previous cytokine therapy only. Sorafenib and infliximab were administered according to standard schedules. The study had two phases: in phase I, the safety and toxicity of the combination of full-dose sorafenib and two dose levels of infliximab were evaluated in three and three patients, respectively, and in phase II, further safety, toxicity and efficacy data were collected in an expanded patient population. RESULTS: Acceptable safety was reported for the first three patients (infliximab 5 mg kg⁻¹) in phase 1. Sorafenib 400 mg twice daily and infliximab 10 mg kg⁻¹ were administered to a total of 13 patients (three in phase 1 and 10 in phase 2). Adverse events included grade 3 hand-foot syndrome (31%), rash (25%), fatigue (19%) and infection (19%). Although manageable, toxicity resulted in 75% of the patients requiring at least one dose reduction and 81% requiring at least one dose delay of sorafenib. Four patients were progression-free at 6 months (PFS₆ 31%); median PFS and overall survival were 6 and 14 months, respectively. CONCLUSION: Sorafenib and infliximab can be administered in combination, but a significant increase in the numbers of adverse events requiring dose adjustments of sorafenib was observed. There was no evidence of increased efficacy compared with sorafenib alone in advanced RCC. The combination of sorafenib and infliximab does not warrant further evaluation in patients with advanced RCC..

Pickering, L.M., Constantinidou, A., Larkin, J.M., Sohaib, S.A., Khatri, P., Nathan, P.D., Vinayan, A., Ferguson, T., St Rose, S. & Gore, M.E., et al. (2010). Sunitinib treatment for longer than 2 years for renal cell carcinoma. Journal of clinical oncology, Vol.28 (15).

Larkin, J.M., Hess, V., Pickering, L.M., Ferguson, T., Forrest, R. & Gore, M.E. (2010). Symptomatic brain metastases from renal cell carcinoma during treatment with sunitinib or sorafenib. Journal of clinical oncology, Vol.28 (15).

Swanton, C., Juul, N., Larkin, J.M., Eklund, A., Li, Q., Desmedt, C., Sotiriou, C., Pusztal, L. & Szallasi, Z. (2010). Use of an RNA interference screen-derived mitotic and ceramide pathway metagene to predict response to paclitaxel combination chemotherapy in primary breast cancer. Journal of clinical oncology, Vol.28 (15).

Larkin, J. & Gore, M. (2010). Is advanced renal cell carcinoma becoming a chronic disease?. Lancet, Vol.376 (9741), pp. 574-575.

Fisher, R.A. & Larkin, J. (2010). Malignant melanoma (metastatic). Bmj clin evid, Vol.2010. show abstract

Larkin, J.M., Pyle, L.M. & Gore, M.E. (2010). Fatigue in renal cell carcinoma: the hidden burden of current targeted therapies. Oncologist, Vol.15 (11), pp. 1135-1146. show abstract

Swanton, C., Larkin, J.M., Gerlinger, M., Eklund, A.C., Howell, M., Stamp, G., Downward, J., Gore, M., Futreal, P.A., Escudier, B., et al. (2010). Predictive biomarker discovery through the parallel integration of clinical trial and functional genomics datasets. Genome medicine, Vol.2.

Pickering, L.M., Pyle, L. & Larkin, J.M. (2009). Sunitinib is superior to interferon alpha with respect to quality of life for patients with renal cell carcinoma. Nat clin pract oncol, Vol.6 (1), pp. 6-7. show abstract

Larkin, J.M., Clarke, R.E. & Pickering, L.M. (2009). Everolimus (RAD001) in the treatment of advanced renal cell carcinoma: biology and pathways. Medical oncology, Vol.26, pp. 40-45.

Larkin, J.M., Kipps, E.L., Powell, C.J. & Swanton, C. (2009). Systemic therapy for advanced renal cell carcinoma. Ther adv med oncol, Vol.1 (1), pp. 15-27. show abstract

Sternberg, C.N., Bellmunt, J., Gruenwald, V., Larkin, J. & Mulders, P. (2009). Advances in the Management of Metastatic Renal Cell Cancer. European urology supplements, Vol.8 (9), pp. 758-761.

Larkin, J. & Gore, M. (2009). HEALTH POLICY The UK 'postcode lottery' in renal cell carcinoma. Nature reviews urology, Vol.6 (12), pp. 636-638.

Miller, R.E. & Larkin, J.M. (2009). Combination systemic therapy for advanced renal cell carcinoma. Oncologist, Vol.14 (12), pp. 1218-1224. show abstract

Josephs, D.H., Hutson, T.E., Pickering, L.M., Larkin, J.M., Choueiri, T.K., Patel, T.V., Mcdermott, D.F., Powles, T., Harper, P.G. & Chowdhury, S., et al. (2009). Efficacy and toxicity of sunitinib in patients with metastatic renal cell carcinoma (mRCC) with severe renal impairment or on haemodialysis. J clin oncol, Vol.27 (15_suppl), p. 5109. show abstract

Carden, C.P., Myerson, J.S., Popat, S., Montes, A., Larkin, J.M., Benson, M.J. & O'Brien, M.E. (2008). Good vibrations and the power of positron thinking: positron emission tomography and endoscopic ultrasound in staging of mesothelioma-two case reports. J thorac oncol, Vol.3 (5), pp. 539-541.

Carden, C.P., Larkin, J.M. & Rosenthal, M.A. (2008). What is the risk of intracranial bleeding during anti-VEGF therapy?. Neuro oncol, Vol.10 (4), pp. 624-630. show abstract

Chowdhury, S., Larkin, J.M. & Gore, M.E. (2008). Recent advances in the treatment of renal cell carcinoma and the role of targeted therapies. European journal of cancer, Vol.44 (15), pp. 2152-2161.

Dernedde, U., Chan, S., Sykes, H., Oakley, C., Larkin, J., Popat, S., Gilbert, D., Jones, L. & Chowdhury, S. (2008). South West London Cancer Network (SWLCN) audit of patients with chemotherapy-induced febrile neutropenia (CIFN). Journal of clinical oncology, Vol.26 (15).

Larkin, J. & Gore, M. (2008). Malignant melanoma (metastatic). Bmj clin evid, Vol.2008. show abstract

Larkin, J.M. & Porter, C.D. (2007). Complement insufficiency limits efficacy in a xenograft model of hyperacute rejection for cancer therapy. Cancer immunology immunotherapy, Vol.56 (1), pp. 60-69.

Fearfield, L.A., Larkin, J.M., Rowe, A., A'Hern, R., Fisher, C., Francis, N., MacKie, R., McCann, B., Gore, M.E. & Bunker, C.B., et al. (2007). Expression of p16, CD95, CD95L and Helix pomatia agglutinin in relapsing and nonrelapsing very thin melanoma. Brit j dermatol, Vol.156 (3), pp. 440-447. show abstract

Larkin, J.M. (2007). Patupilone Antimitotic drug, microtubule-stabilizing agent, oncolytic. Drugs of the future, Vol.32 (4), pp. 323-336.

Larkin, J.M. & Kaye, S.B. (2007). Potential clinical applications of epothilones: a review of phase II studies. Ann oncol, Vol.18 Suppl 5, pp. v28-v34. show abstract

Larkin, J.M., Chowdhury, S. & Gore, M.E. (2007). Drug insight: advances in renal cell carcinoma and the role of targeted therapies. Nat clin pract oncol, Vol.4 (8), pp. 470-479. show abstract

Larkin, J.M., Hughes, S.A., Beirne, D.A., Patel, P.M., Gibbens, I.M., Bate, S.C., Thomas, K., Eisen, T.G. & Gore, M.E. (2007). A Phase I/II study of lomustine and temozolomide in patients with cerebral metastases from malignant melanoma. British journal of cancer, Vol.96 (1), pp. 44-48.

Larkin, J.M. & Eisen, T. (2006). Renal cell carcinoma and the use of sorafenib. Ther clin risk manag, Vol.2 (1), pp. 87-98. show abstract

Larkin, J.M., Norsworth, P.J., A'Hern, R.P., Eisen, T.G., Gore, M.E. & Porter, C.D. (2006). Anti-alpha Gal-dependent complement-mediated cytotoxicity in metastatic melanoma. Melanoma res, Vol.16 (2), pp. 157-163. show abstract

Larkin, J.M. & Kaye, S.B. (2006). Epothilones in the treatment of cancer. Expert opin inv drug, Vol.15 (6), pp. 691-702. show abstract

Larkin, J.M. & Eisen, T. (2006). Kinase inhibitors in the treatment of renal cell carcinoma. Crit rev oncol hematol, Vol.60 (3), pp. 216-226. show abstract

Larkin, J.M. & Porter, C.D. (2005). Mice are unsuitable for modelling ABO discordance despite strain-specific A cross-reactive natural IgM. British journal of haematology, Vol.130 (2), pp. 310-317.

Larkin, J.M. & Gore, M.E. (2005). The MRC randomised-controlled trial of interferon-alpha, interleukin-2 and 5-fluorouracil vs interferon-alpha alone in patients with advanced renal cell carcinoma (RE04): Rationale and progress. Clinical oncology, Vol.17 (5), pp. 319-321.

Kolomainen, D.F., Larkin, J.M., Badran, M., A'Hern, R.P., King, D.M., Fisher, C., Bridges, J.E., Blake, P.R., Barton, D.P., Shepherd, J.H., et al. (2002). Epithelial ovarian cancer metastasizing to the brain: a late manifestation of the disease with an increasing incidence. J clin oncol, Vol.20 (4), pp. 982-986. show abstract

Gulati, S., Martinez, P., Joshi, T., Birbak, N.J., Santos, C.R., Rowan, A.J., Pickering, L., Gore, M., Larkin, J., Szallasi, Z., et al. Systematic Evaluation of the Prognostic Impact and Intratumour Heterogeneity of Clear Cell Renal Cell Carcinoma Biomarkers. European urology, . show abstract

Henrion, M.Y., Purdue, M.P., Scelo, G., Broderick, P., Frampton, M., Ritchie, A., Meade, A., Li, P., McKay, J., Johansson, M., et al. Common Variation at 1q24 1 (ALDH9A1) Is a Potential Risk Factor for Renal Cancer. Plos one, Vol.10 (3), pp. e0122589-e0122589.

Biondo, A., Alexander, H., Khabra, K., Pickering, L., Gore, M. & Larkin, J. Pazopanib-Induced Alopecia, an Underestimated Toxicity?. Frontiers in oncology, Vol.5.

Argyropulo-Palmer, M., Jenkins, A., Theti, D.S., Larkin, J. & Montgomery, D. Sunitinib in Metastatic Renal Cell Carcinoma: A Systematic Review of UK Real World Data. Frontiers in oncology, Vol.5.

Larkin, J., Hatswell, A.J., Nathan, P., Lebmeier, M. & Lee, D. The Predicted Impact of Ipilimumab Usage on Survival in Previously Treated Advanced or Metastatic Melanoma in the UK. Plos one, Vol.10 (12), pp. e0145524-e0145524.

Reynolds, A., bridgeman, V., vermeulen, P., foo, S., bilezc, A., daley, F., kostaras, E., nathan, M., wan, E., frentzas, S., et al. Vessel co-option is common in human lung metastases and mediates resistance to anti-angiogenic therapy in preclinical lung metastasis models. Journal of pathology, .

O’Reilly, A. & Larkin, J. Lenvatinib for use in combination with everolimus for the treatment of patients with advanced renal cell carcinoma following one prior anti-angiogenic therapy. Expert review of clinical pharmacology, , pp. 1-12.

Spain, L., Walls, G., Julve, M., O’Meara, K., Schmid, T., Kalaitzaki, E., Turajlic, S., Gore, M., Rees, J. & Larkin, J., et al. Neurotoxicity from immune-checkpoint inhibition in the treatment of melanoma: a single centre experience and review of the literature. Annals of oncology, , pp. mdw558-mdw558.

Conferences

Hirata, E., Girotti, M.R., Viros, A., Hooper, S., Spencer-Dene, B., Matsuda, M., Larkin, J., Marais, R. & Sahai, E. (2015). Intravital imaging reveals how BRaf inhibition generates drug tolerant microenvironments., JOURNAL OF NUCLEAR MEDICINE, Vol.56 (2), p.26.

Ribas, A., Schachter, J., Long, G.V., Arance, A., Grob, J.J., Mortier, L., Daud, A., Carlino, M.S., McNeil, C., Lotem, M., et al. (2015). Abstract CT101: Phase III study of pembrolizumab (MK-3475) versus ipilimumab in patients with ipilimumab-naive advanced melanoma, Presented at Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA, Clinical Trials, .

Sinha, R., Larkin, J., Gore, M.E. & Fearfield, L. (2015). Incidence and management of skin-related adverse events associated with vemurafenib in BRAF V600E-positive metastatic melanoma: a 3-year retrospective cohort study of 107 patients, BRITISH JOURNAL OF DERMATOLOGY, Vol.173, p.5.

Thomas, C., Mortimer, P.S., Larkin, J.M., Basu, T.N., Gore, M.E. & Fearfield, L. (2015). Skin toxicity and oedema in metastatic melanoma treated with mitogen-activated protein kinase kinase inhibitors, BRITISH JOURNAL OF DERMATOLOGY, Vol.173, pp.59-60.

Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J.J., Cowey, C.L., Lao, C.D., Wagstaff, J., Hogg, D., Hill, A., Carlino, M.S., et al. (2015). 3303 Efficacy and safety in key patient subgroups of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naïve patients with advanced melanoma (MEL) (CheckMate 067), European Journal of Cancer, Vol.51, pp.S664-S665.

McArthur, G., Larkin, J., Dréno, B., Ascierto, P., Liszkay, G., Maio, M., Mandal´, M., Demidov, L., Stroyakovskiy, D., Thomas, L., et al. (2015). 25LBA Impact of baseline genetic heterogeneities on progression-free survival (PFS) in patients (pts) with advanced BRAFV600-mutated melanoma treated with cobimetinib (COBI) + vemurafenib (VEM) in the phase 3 coBRIM study, European Journal of Cancer, Vol.51, pp.S722-S723.

Glen, H., Hsieh, J., Michaelson, M.D., Kim, H.J., Sachdev, P., Kadowaki, T., Funahashi, Y., Larkin, J. & Motzer, R. (2015). 432 Correlative analyses of serum biomarkers and clinical outcomes in the phase 2 study of lenvatinib, everolimus, and the combination, in patients with metastatic renal cell carcinoma following 1 VEGF-targeted therapy, European Journal of Cancer, Vol.51, p.S89.

Wolchok, J.D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J., Cowey, C.L., Lao, C.D., Schadendorf, D., Ferrucci, P.F., Smylie, M., et al. (2015). CheckMate 067: a phase III randomized double-blind study of nivolumab (NIVO) monotherapy or NIVO combined with ipilimumab (IPI) versus IPI monotherapy in previously untreated patients (pts) with advanced melanoma (MEL), ANNALS OF ONCOLOGY, Vol.26, p.28.

Hammers, H.J., Plimack, E.R., Sternberg, C., McDermott, D.F., Larkin, J.M., Ravaud, A., Rini, B.I., Sharma, P., Bhagavatheeswaran, P., Gagnier, P., et al. (2015). CheckMate 214: A phase III, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in patients with previously untreated metastatic renal cell carcinoma., Journal of Clinical Oncology, Vol.33 (15_suppl), p.TPS4578.

De La Cruz-Merino, L., Di Guardo, L., Grob, J.-., Venosa, A., Larkin, J.M., McArthur, G.A., Ribas, A., Eng, S., Hsu, J.J., Barteselli, G., et al. (2015). Clinical features of cobimetinib (COBI)-associated serous retinopathy (SR) in BRAF-mutated melanoma patients (pts) treated in the coBRIM study, JOURNAL OF CLINICAL ONCOLOGY, Vol.33 (15).

Larkin, J.M., Yan, Y., McArthur, G.A., Ascierto, P.A., Liszkay, G., Maio, M., Mandala, M., Demidov, L.V., Stroyakovskiy, D., Thomas, L., et al. (2015). Update of progression-free survival (PFS) and correlative biomarker analysis from coBRIM: Phase III study of cobimetinib (cobi) plus vemurafenib (vem) in advanced BRAF-mutated melanoma., JOURNAL OF CLINICAL ONCOLOGY, Vol.33 (15).

Colomba, E., Albiges, L., Le Teuff, G., Eisen, T., Stewart, G., Fife, K., Srinivasan, A., Larkin, J.M., Biondo, A., Pickering, L.M., et al. (2015). Metastatic chromophobe renal cell carcinoma treated with target therapies: A Renal Cross Chanel Group (RCCG) study., JOURNAL OF CLINICAL ONCOLOGY, Vol.33 (15).

Long, G.V., Stroyakovskiy, D., Gogas, H., Levchenko, E., De Braud, F.G., Larkin, J.M., Garbe, C., Jouary, T., Hauschild, A., Grob, J.J., et al. (2015). Overall survival in COMBI-d, a randomized, double-blinded, phase III study comparing the combination of dabrafenib and trametinib with dabrafenib and placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAF V600E/Kmutation-positive cutaneous melanoma., Journal of Clinical Oncology, Vol.33 (15_suppl), p.102.

Wolchok, J.D., Chiarion-Sileni, V., Gonzalez, R., Rutkowski, P., Grob, J.J., Cowey, C.L., Lao, C.D., Schadendorf, D., Ferrucci, P.F., Smylie, M., et al. (2015). Efficacy and safety results from a phase III trial of nivolumab (NIVO) alone or combined with ipilimumab (IPI) versus IPI alone in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067)., JOURNAL OF CLINICAL ONCOLOGY, Vol.33 (15).

Dreno, B., Bartley, K., Ascierto, P.A., Atkinson, V., Liszkay, G., Maio, M., Mandala, M., Demidov, L.V., Stroyakovskiy, D., Thomas, L., et al. (2015). Quality-of-life (QOL) assessment in patients (pts) with metastatic melanoma receiving vemurafenib (V) and cobimetinib (C)., JOURNAL OF CLINICAL ONCOLOGY, Vol.33 (15).

Motzer, R., Hutson, T., Glen, H., Michaelson, D., Molina, A.M., Eisen, T., Jassem, J., Zolnierek, J., Maroto, P., Mellado, B., et al. (2015). Randomized phase II, three-arm trial of lenvatinib (LEN), everolimus (EVE), and LEN+EVE in patients (pts) with metastatic renal cell carcinoma (mRCC)., Journal of Clinical Oncology, Vol.33 (15_suppl), p.4506.

Weber, J.S., Antonia, S.J., Topalian, S.L., Schadendorf, D., Larkin, J.M., Sznol, M., Liu, H.Y., Waxman, I. & Robert, C. (2015). Safety profile of nivolumab (NIVO) in patients (pts) with advanced melanoma (MEL): A pooled analysis., JOURNAL OF CLINICAL ONCOLOGY, Vol.33 (15).

Flechsig, S., Wulf-Goldenberg, A., Schmees, C., Jandrig, B., Hennenlotter, J., Bedke, J., Schostak, M., Crockford, A., Gerlinger, M., Larkin, J., et al. (2014). Abstract 1192: Establishment and characterization of a new patient-derived renal cell carcinoma xenograft panel, Presented at Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA, Tumor Biology, .

Weber, J.S., Minor, D.R., D'Angelo, S.P., Hodi, F.S., Gutzmer, R., Neyns, B., Hoeller, C., Khushalani, N.I., Miller, W.H., Grob, J.-., et al. (2014). A PHASE 3 RANDOMIZED, OPEN-LABEL STUDY OF NIVOLUMAB (ANTI-PD-1; BMS-936558; ONO-4538) VERSUS INVESTIGATOR'S CHOICE CHEMOTHERAPY (ICC) IN PATIENTS WITH ADVANCED MELANOMA AFTER PRIOR ANTI-CTLA-4 THERAPY, ANNALS OF ONCOLOGY, Vol.25.

Larkin, J. & Okines, A. (2014). PRECISION MEDICINE IN KIDNEY CANCER AND CLINICAL TRIAL DESIGNS, ANNALS OF ONCOLOGY, Vol.25.

Powles, T., Hawkins, R., Ralph, C., Larkin, J., Jones, R.J., Chowdhury, S., Boleti, E., Fife, K., Bahl, A., Crabb, S., et al. (2014). A RANDOMISED PHASE II STUDY OF CEDIRANIB WITH OR WITHOUT SRC INHIBITION (SARACATINIB) IN METASTATIC CLEAR CELL RENAL CANCER (RCC) PATIENTS RESISTANT TO VEGF TARGETED THERAPY, ANNALS OF ONCOLOGY, Vol.25.

Hammers, H., Sternberg, C., Mcdermott, D.F., Larkin, J., Ravaud, A., Rini, B., Sharma, P., Bhagavatheeswaran, P., Gagnier, P. & Motzer, R., et al. (2014). A phase 3, randomized, open-label study of nivolumab combined with ipilimumab versus sunitinib monotherapy in subjects with previously untreated metastatic renal cell carcinoma, BJU INTERNATIONAL, Vol.114, p.9.

Middleton, M., Rasco, D.W., Olszanski, A.J., Corrie, P., Lorigan, P., Plummer, R., Larkin, J., Pavlick, A., Zhou, X., Yuan, Z., et al. (2014). First-in-human phase 1 study of MLN2480, an investigational oral pan-RAF kinase inhibitor, in patients (pts) with relapsed or refractory solid tumors, including BRAF/NRAS-mutant melanoma, EUROPEAN JOURNAL OF CANCER, Vol.50, p.117.

Fisher, R.A., Rowan, A., Stares, M., Webster-Smith, M.F., Lewis, R., Kilburn, L.S., Nicol, D., Stewart, G., Michael, A., Vasudev, N., et al. (2014). A-PREDICT: A phase II study of axitinib in patients with metastatic renal cell cancer unsuitable for nephrectomy (CRUKE/11/061)., Journal of Clinical Oncology, Vol.32 (15_suppl), p.TPS4597.

Gogas, H., Schadendorf, D., Dummer, R., Garbe, C., Lebbe, C., Nathan, P.D., Larkin, J.M., Haydon, A.M., Bafaloukos, D. & Robert, C., et al. (2014). Vemurafenib treatment in patients with BRAF-mutated melanoma failing MEK inhibition with trametinib., Journal of Clinical Oncology, Vol.32 (15_suppl), p.9061.

Piperno-Neumann, S., Kapiteijn, E., Larkin, J.M., Carvajal, R.D., Luke, J.J., Seifert, H., Roozen, I., Zoubir, M., Ramkumar, T., Emery, C., et al. (2014). Landscape of genetic alterations in patients with metastatic uveal melanoma., Journal of Clinical Oncology, Vol.32 (15_suppl), p.9043.

Long, G.V., Stroyakovsky, D.L., Gogas, H., Levchenko, E., de Braud, F., Larkin, J.M., Garbe, C., Jouary, T., Hauschild, A., Grob, J.J., et al. (2014). COMBI-d: A randomized, double-blinded, Phase III study comparing the combination of dabrafenib and trametinib to dabrafenib and trametinib placebo as first-line therapy in patients (pts) with unresectable or metastatic BRAFV600E/K mutation-positive cutaneous melanoma, Journal of Clinical Oncology, Vol.32 (15_suppl), p.9011.

Piperno-Neumann, S., Kapiteijn, E., Larkin, J.M., Carvajal, R.D., Luke, J.J., Seifert, H., Roozen, I., Zoubir, M., Yang, L., Choudhury, S., et al. (2014). Phase I dose-escalation study of the protein kinase C (PKC) inhibitor AEB071 in patients with metastatic uveal melanoma., Journal of Clinical Oncology, Vol.32 (15_suppl), p.9030.

Rini, B.I., Dorff, T.B., Elson, P., Suarez, C., Humbert, J., Pyle, L., Larkin, J.M. & Plimack, E.R. (2014). A prospective observational study of metastatic renal cell carcinoma (mRCC) prior to initiation of systemic therapy., Journal of Clinical Oncology, Vol.32 (15_suppl), p.4520.

Salmon, N., Fearfield, L.A., Gore, M. & Larkin, J. (2013). Metastatic basal cell carcinoma, BRITISH JOURNAL OF DERMATOLOGY, Vol.169, p.20.

Larkin, J., Paine, A., Foley, G., Mitchell, S.A. & Chen, C. (2013). First-line treatment in the management of advanced renal cell carcinoma: Systematic review and network meta-analysis, EUROPEAN JOURNAL OF CANCER, Vol.49, p.S656.

Gogas, H., Schadendorf, D., Dummer, R., Garbe, C., Lebbe, C., Nathan, P., Larkin, J., Haydon, A., Bafaloukos, D. & Robert, C., et al. (2013). Vemurafenib treatment in patients with BRAF mutated melanoma failing MEK inhibition with trametinib, EUROPEAN JOURNAL OF CANCER, Vol.49, pp.S866-S867.

Das Thakur, M., Fisher, R., Salangsang, F., Landman, A., Sellers, W., Pryer, N., Levesque, M.P., Dummer, R., Gore, M., Larkin, J., et al. (2013). Modeling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance., CANCER RESEARCH, Vol.73 (8).

Molina, A.M., Hutson, T.E., Larkin, J.M., Gold, A., Andresen, C., Wood, K., Motzer, R.J. & Michaelson, M.D. (2013). A phase Ib clinical trial of the multitargeted kinase inhibitor lenvatinib (E7080) in combination with everolimus for treatment of metastatic renal cell carcinoma (RCC), JOURNAL OF CLINICAL ONCOLOGY, Vol.31 (6).

Blank, C.U., Kelderman, S., van Tinteren, H., Heemskerk, B., van den Brom, R., Hospers, G.A., van den Eertwegh, A.J., Kapiteijn, E., De Groot, J.W., Jansen, R.L., et al. (2013). Serum lactate dehydrogenase (LDH) as a prognostic selection criterion for ipilimumab treatment in metastatic melanoma, JOURNAL OF CLINICAL ONCOLOGY, Vol.31 (15).

Larkin, J.M., Del Vecchio, M., Ascierto, P.A., Schachter, J., Garbe, C., Neyns, B., Mandala, M., Lorigan, P., Miller, W.H., Guminski, A.D., et al. (2013). Open-label, multicenter safety study of vemurafenib in patients with BRAF(V600) mutation-positive metastatic melanoma, JOURNAL OF CLINICAL ONCOLOGY, Vol.31 (15).

Ahmad, S., Qian, W., Ellis, S.G., Khattak, M.A., Gupta, A., Thillai, K., Board, R.E., Nobes, J., Dalgleish, A., Grumett, S.A., et al. (2013). Ipilimumab in the real world: The UK expanded access programme (EAP) experience in advanced melanoma., JOURNAL OF CLINICAL ONCOLOGY, Vol.31 (15).

Sacco, J.J., Nathan, P.D., Danson, S., Lorigan, P., Nicholson, S., Ottensmeier, C., Corrie, P., Steven, N., Goodman, A., Larkin, J.M., et al. (2013). Sunitinib versus dacarbazine as first-line treatment in patients with metastatic uveal melanoma, JOURNAL OF CLINICAL ONCOLOGY, Vol.31 (15).

Gupta, A., Love, S., Schuh, A., Collins, L., Thomason, A., Asher, R., Lisle, R., Churchman, M., Shanyinde, M., Plummer, R., et al. (2013). DOC-MEK: A double-blind randomized phase II trial of docetaxel with or without selumetinib (AZD6244; ARRY-142886) in wt BRAF advanced melanoma, JOURNAL OF CLINICAL ONCOLOGY, Vol.31 (15).

Schadendorf, D., Flaherty, K., Hersey, P., Nathan, P.D., Garbe, C., Milhem, M.M., Demidov, L.V., Hassel, J.C., Rutkowski, P., Mohr, P., et al. (2013). Tumor-specific circulating cell-free DNA (cfDNA) to predict clinical outcome in BRAF V600 mutation-positive melanoma patients (pts) treated with the MEK inhibitor trametinib (T) or chemotherapy (C), JOURNAL OF CLINICAL ONCOLOGY, Vol.31 (15).

Hutson, T.E., Bukowski, R., Rini, B.I., Gore, M.E., Larkin, J.M., Figlin, R.A., Barrios, C.H., Escudier, B., Lin, X., Fly, K., et al. (2012). A pooled analysis of the efficacy and safety of sunitinib in elderly patients with metastatic renal cell carcinoma (mRCC), BJU INTERNATIONAL, Vol.109, pp.5-6.

Sinha, R., Edmonds, K., Newton-Bishop, J.A., Gore, M., Larkin, J. & Fearfield, L.A. (2012). Cutaneous adverse events associated with vemurafenib in patients with BRAF V600E mutation-positive metastatic melanoma: an observational study of 30 treated patients and presentation of a management algorithm, BRITISH JOURNAL OF DERMATOLOGY, Vol.167, pp.9-10.

Khattak, M.A., Edmonds, K., Khabra, K., Sohaib, A., Pennert, K., Pickering, L., Gore, M.E. & Larkin, J. (2012). INTERIM RESULTS OF A PHASE II STUDY OF SUNITINIB AND LOW DOSE METRONOMIC CYCLOPHOSPHAMIDE IN ADVANCED RENAL CELL CANCER, ANNALS OF ONCOLOGY, Vol.23, pp.273-274.

Molina, A.M., Hutson, T.E., Larkin, J., Gold, A., Andresen, C., Wood, K., Motzer, R.J. & Michaelson, M.D. (2012). A PHASE IB CLINICAL TRIAL OF THE MULTITARGETED KINASE INHIBITOR LENVATINIB (E7080) IN COMBINATION WITH EVEROLIMUS FOR TREATMENT OF METASTATIC RENAL CELL CARCINOMA (RCC), ANNALS OF ONCOLOGY, Vol.23, p.269.

Proskorovsky, I., Benedict, A., Negrier, S., Larkin, J., Sandin, R. & Chen, C. (2012). AXITINIB (AXI) AND EVEROLIMUS (EVE) IN THE TREATMENT (TX) OF SUNITINIB-REFRACTORY (SU-R) PATIENTS (PTS) WITH METASTATIC RENAL CELL CARCINOMA (MRCC): RESULTS OF A SIMULATED TX COMPARISON (STC) ANALYSES, ANNALS OF ONCOLOGY, Vol.23, p.279.

Blank, C., Del Vecchio, M., Ascierto, P.A., Queirolo, P., Hauschild, A., Arance, A., Brown, M., Mitchell, L., Veronese, L. & Larkin, J., et al. (2012). AN OPEN-LABEL, MULTICENTRE SAFETY STUDY OF VEMURAFENIB IN PATIENTS WITH METASTATIC MELANOMA, ANNALS OF ONCOLOGY, Vol.23, p.366.

Chowdhury, S. & Larkin, J. (2012). EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA WHO PROGRESS AFTER INITIAL VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-TYROSINE KINASE INHIBITOR (VEGFR-TKI) THERAPY: UK RESULTS FROM THE REACT TRIAL ON BEHALF OF THE UK REACT INVESTIGATORS, ANNALS OF ONCOLOGY, Vol.23, pp.271-272.

Shaw, H., Larkin, J., Corrie, P., Ellis, S., Nobes, J., Marshall, E., Kumar, S., Danson, S., Plummer, R. & Nathan, P., et al. (2012). IPILIMUMAB FOR ADVANCED MELANOMA IN AN EXPANDED ACCESS PROGRAMME (EAP): OCULAR, MUCOSAL AND ACRAL SUBTYPE UK EXPERIENCE, ANNALS OF ONCOLOGY, Vol.23, p.374.

Pedersen, J.V., Benson, C., Tunariu, N., Mitchell, S., Fisher, C., Thway, K., Larkin, J.M., Scurr, M. & Judson, I.R. (2012). A retrospective study from the Royal Marsden Hospital (RMH) of patients with malignant perivascular epithelioid cell tumors (PEComa) receiving treatment with sirolimus (SI) or temsirolimus (TSI), JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (15).

Larkin, J.M., Queirolo, P., Arance, A.M., Brown, M.P., Hauschild, A., Del Vecchio, M., McArthur, G.A., Neyns, B., Becker, J.C., Hansson, J., et al. (2012). An open-label, multicenter safety study of vemurafenib (PLX4032, RO5185426) in patients with metastatic melanoma., JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (15).

Robert, C., Flaherty, K.T., Hersey, P., Nathan, P.D., Garbe, C., Milhem, M.M., Demidov, L.V., Hassel, J.C., Rutkowski, P., Mohr, P., et al. (2012). METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS) compared with chemotherapy (C) in patients (pts) with BRAF(V600/k) mutant advanced or metastatic melanoma (MM), JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (15).

Chapman, P.B., Hauschild, A., Robert, C., Larkin, J.M., Haanen, J.B., Ribas, A., Hogg, D., Hamid, O., Ascierto, P.A., Testori, A., et al. (2012). Updated overall survival (OS) results for BRIM-3, a phase III randomized, open-label, multicenter trial comparing BRAF inhibitor vemurafenib (vem) with dacarbazine (DTIC) in previously untreated patients with BRAF(V600E)-mutated melanoma., JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (15).

Molina, A.M., Motzer, R.J., Hutson, T.E., Larkin, J.M., Gold, A., Andresen, C., Wood, K. & Michaelson, M.D. (2012). Treatment of refractory metastatic renal cell carcinoma (RCC) with lenvatinib (E7080) and everolimus, JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (15).

Robert, C., Flaherty, K.T., Hersey, P., Nathan, P.D., Garbe, C., Milhem, M.M., Demidov, L.V., Hassel, J.C., Rutkowski, P., Mohr, P., et al. (2012). METRIC phase III study: Efficacy of trametinib (T), a potent and selective MEK inhibitor (MEKi), in progression-free survival (PFS) and overall survival (OS), compared with chemotherapy (C) in patients (pts) with BRAF(V600E/K) mutant advanced or metastatic melanoma (MM), JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (18).

Marshall, E., Coupland, S., Corrie, P., Damato, B., Danson, S., Dobson, L., Evans, T.R., Goodman, A., Kalirai, H., Jones, S., et al. (2012). A randomized phase II study of sunitinib versus dacarbazine in the treatment of patients with metastatic uveal melanoma., JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (15).

Plimack, E.R., Nemec, C., Elson, P., Suarez, C., Dorff, T.B., Larkin, J.M., McAleer, C., Nunez, I., Fisher, R.A. & Rini, B.I., et al. (2012). An observational study of metastatic renal cell carcinoma patients prior to initiation of initial systemic therapy, JOURNAL OF CLINICAL ONCOLOGY, Vol.30 (15).

Dudderidge, T.J., Beatty, J., Larkin, J., Gore, M. & Christmas, T.J. (2011). Surgery for loco-regional recurrence after nephrectomy for renal cell carcinoma (RCC): outcomes after initial incomplete resection and implantational recurrences, BJU INTERNATIONAL, Vol.108, p.42.

Sinha, R., Fearfield, L. & Larkin, J. (2011). A case series of BRAF V600E inhibitor (PLX4032) related cutaneous eruptions in metastatic melanoma, BRITISH JOURNAL OF DERMATOLOGY, Vol.165, p.19.

Larkin, J., Blank, C., Bono, P., Kim, D., Panneerselvam, A. & Gruenwald, V. (2011). The REACT Expanded-access Program of Everolimus in Patients With Metastatic Renal Cell Carcinoma Refractory to VEGF-targeted Therapy: Subgroup Analyses by Prior Therapy, EUROPEAN JOURNAL OF CANCER, Vol.47, p.S519.

Albiges, L., Iacovelli, R., Porta, C., Houede, N., Laguerre, B., Procopio, G., Lheureux, S., Larkin, J., Negrier, S. & Escudier, B., et al. (2011). Prognosis of Patients With Metastatic Renal Cell Carcinoma (mRCC) With Primary Resistance to Sunitinib: Is There Any Active Treatment?, EUROPEAN JOURNAL OF CANCER, Vol.47, p.S518.

Blank, C., Bono, P., Larkin, J., Kim, D., Panneerselvam, A. & Gruenwald, V. (2011). Safety and Efficacy of Everolimus in Patients With Non-clear Cell Renal Cell Carcinoma Refractory to VEGF-targeted Therapy - a Subgroup Analysis of the REACT Expanded-access Program, EUROPEAN JOURNAL OF CANCER, Vol.47, p.S516.

Larkin, J.M., Turajlic, S., Nathan, P.D., Lorigan, P., Stamp, G., de Castro, D.G., Martin, N., Griffiths, J., Edmonds, K., Sarker, S., et al. (2011). A phase II trial of nilotinib in the treatment of patients with KIT mutated advanced acral and mucosal melanoma (NICAM)., JOURNAL OF CLINICAL ONCOLOGY, Vol.29 (15).

Grunwald, V., Miller, K., Machiels, J., Lee, S., Larkin, J., Yuan, R., Rosamilia, M., Booth, J. & Karakiewicz, P. (2010). AN INTERNATIONAL EXPANDED ACCESS PROGRAM (EAP) OF EVEROLIMUS IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA (MRCC) WHO ARE INTOLERANT OF OR HAVE PROGRESSED AFTER PRIOR VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-TYROSINE KINASE INHIBITOR (VEGFR-TKI) THERAPY, ANNALS OF ONCOLOGY, Vol.21, p.274.

Christmas, T.J., Dudderidge, T., Beatty, J., Larkin, J., Gore, M. & Moat, N. (2010). Long Term Results of Surgery for Renal Tumours with Venous Extension, BJU INTERNATIONAL, Vol.106 (1), p.47.

Christmas, T.J., Agrawal, S., Savage, P., Larkin, J. & Gore, M. (2010). Laparoscopic and Open Radical Nephrectomy for Renal Carcinoma. Are They Oncologically Equivalent? A Comparison Using Loco-Regional Recurrence Data, BJU INTERNATIONAL, Vol.106 (1), p.46.

Gerlinger, M., Horswell, S., Larkin, J., Rowan, A.J., Martinez, P., Varela, I., Santos, C.R., Fisher, R., Salm, M.P., Szallasi, Z., et al. Intratumor heterogeneity in clear cell renal cell carcinoma (ccRCC): Multi-region sequencing redefines the mutational landscape of ccRCCs, Presented at AACR Annual Meeting, Washington. .

Types of Publications

Journal Articles

Conferences

In this section